Injectable Formulation

ABSTRACT

An object of the present invention is to provide a sustained-release injectable preparation which is in a medication administration form that can provide the effect of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one for a prolonged period of time, the preparation releasing a therapeutically effective amount of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one for at least one week. The present invention provides an injectable preparation containing 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-3H-quinolin-2-one or a salt thereof as an active ingredient, which releases the active ingredient in such a manner that its blood concentration is maintained for at least one week.

TECHNICAL FIELD

The present invention relates to an injectable preparation comprising7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-oneor a salt thereof.

BACKGROUND ART

7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one(hereinafter also referred to as “Compound (I)”) is a benzothiophenecompound represented by Formula (I):

Compound (I) or salts thereof are known to have serotonin uptakeinhibitory activity (or serotonin re-uptake inhibitory activity) inaddition to dopamine D₂ receptor partial agonistic activity (D₂ receptorpartial agonistic activity), serotonin 5-HT_(2A) receptor antagonisticactivity (5-HT_(2A) receptor antagonistic activity), and adrenaline α₁receptor antagonistic activity (α₁ receptor antagonistic activity)(Patent Literature (PTL) 1). Compound (I) and salts thereof have a widetherapeutic spectrum for central nervous system diseases (particularlyschizophrenia).

CITATION LIST Patent Literature

-   PTL 1: JP2006-316052A

SUMMARY OF INVENTION Technical Problem

In central nervous system diseases such as schizophrenia, a long-actingmedication administration form is useful because it increases patientcompliance, and thereby lowers the relapse rate during treatment.

An object of the present invention is to provide an injectablepreparation that exhibits the effect of Compound (I) or a salt thereoffor a prolonged period of time, is stable even after long-term storage,and can be easily injected. The present invention provides asustained-release injectable preparation that preferably maintains aneffective blood concentration of Compound (I) or a salt thereof for atleast one week.

Solution to Problem

The present inventors conducted extensive research to achieve the aboveobject, and as a result, they found that an injectable preparationhaving a specific composition comprising Compound (I) or a salt thereofas an active ingredient does not form a hard cake even when Compound (I)precipitates, and can be easily re-dispersed by using a simple operationsuch as gentle stirring, and suitably injected. The inventors furtherfound that the injectable preparation having the specific compositioncan exhibit the effect of Compound (I) or a salt thereof for a prolongedperiod of time. In particular, the inventors found that the injectablepreparation can release a therapeutically effective amount of Compound(I) or a salt thereof for at least one week. The present invention hasbeen accomplished upon further study based on this finding, and includesthe inventions listed below.

Item 1. An aqueous suspension comprising secondary particles formed bythe aggregation of particles (primary particles) of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-oneor a salt thereof, the secondary particles having a mean particlediameter (a mean secondary particle diameter) of 1 to 50 μm and beingcontained in a dispersed state.Item 2. The aqueous suspension according to item 1, wherein theparticles of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-oneor a salt thereof have a mean primary particle diameter of 0.1 to 20 μm.Item 3. The aqueous suspension according to item 1 or 2, comprising7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onein an amount of 0.1 to 40 wt %.Item 4. An injectable preparation comprising the aqueous suspensionaccording to any one of items 1 to 3.Item 5. An injectable preparation comprising7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-oneor a salt thereof, a particle binder, and water for injection, theparticle binder being at least one member selected from the groupconsisting of sodium chloride, polyoxyethylene sorbitan fatty acidesters, block copolymers of ethylene oxide and propylene oxide,polyethylene glycols, tocopherol, tocotrienol and esters thereof,tocopherol acetate, tocopherol succinate, benzyl alcohol, poorlywater-soluble polyoxyethylene diol dibenzoate, poorly water-solublepolyoxyethylene diol dimethylsulfonic acid and esters thereof, andbenzyl benzoate.Item 6. The injectable preparation according to item 5, wherein the7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-oneor a salt thereof forms secondary particles and the secondary particleshave a mean secondary particle diameter of 1 to 50 μm.Item 7. The injectable preparation according to item 5 or 6, comprisinga suspension of the7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-oneor a salt thereof in water for injection.Item 8. The injectable preparation according to item 5 or 6, comprisinga precipitate of the7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-2H-quinolin-2-oneor a salt thereof.Item 9. The injectable preparation according to any one of items 5 to 8,wherein the particle binder is at least one member selected from thegroup consisting of sodium chloride, polyoxyethylene (20) sorbitanoleate, polyoxyethylene (160) polyoxypropylene (30) glycol, polyethyleneglycols having an average molecular weight of 200 to 6,000, benzylalcohol, and benzyl benzoate.Item 10. The injectable preparation according to any one of items 4 to9, having a pH of 5 to 8.Item 11. The injectable preparation according to any one of items 4 to10, which is for treating or preventing relapse of schizophrenia,bipolar disorder, or depression.Item 12a. The aqueous suspension according to any one of items 1 to 3,wherein the7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-oneor a salt thereof is a dihydrate of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one.Item 12b. The injectable preparation according to any one of items 4 to11, wherein the7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-oneor a salt thereof is a dihydrate of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one.Item 13a. The aqueous suspension according to claim 12a, comprising atleast one member selected from the group consisting of polyoxyethylenesorbitan fatty acid esters and polyethylene glycols as a particlebinder.Item 13b. The injectable preparation according to claim 12b, comprisingat least one member selected from the group consisting ofpolyoxyethylene sorbitan fatty acid esters and polyethylene glycols as aparticle binder.Item 14. A prefilled syringe that is prefilled with the injectablepreparation according to any one of items 4 to 11, 12b, and 13b.Item A. An injectable preparation comprising7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-oneor a salt thereof as an active ingredient, the preparation releasing theactive ingredient in such a manner that its therapeutically effectiveblood concentration is maintained for at least one week.Item B. The injectable preparation according to item A, furthercomprising a binder.Item C. The injectable preparation according to item A or B, having a pHof 5 to 8.

The injectable preparation of the present invention contains Compound(I) or a salt thereof as an active ingredient. Because the injectablepreparation has a specific composition comprising Compound (I) or a saltthereof as an active ingredient, the active ingredient can be easilyredispersed even when precipitation occurs, and can thus be restored toa state suitable for injection. Further, an effective bloodconcentration of Compound (I) or a salt thereof can be maintained for atleast one week. The injectable preparation of the present invention isused in the form of a suspension including water for injection whenadministered.

In the injectable preparation of the present invention, Compound (I) ora salt thereof forms secondary particles and the secondary particlespreferably have a mean particle diameter (a mean secondary particlediameter) of 1 to 50 μm. Preferably, (particularly beforeadministration), the second particles are suspended in the injectablepreparation.

One preferred mode of the injectable preparation of the presentinvention is an injectable preparation comprising an aqueous suspensioncontaining secondary particles formed by the aggregation of particles(primary particles) of Compound (I) or a salt thereof, the secondaryparticles preferably having a mean particle diameter (a mean secondaryparticle diameter) of 1 to 50 μm and the secondary particles beingsuspended.

The secondary particles more preferably have a mean particle diameter (amean secondary particle diameter) of 2 to 30 μm, still more preferably 3to 20 μm, even more preferably 4 to 17 μm, yet more preferably 5 to 15μm, and particularly preferably 5 to 12 μm.

Because the injectable preparation of the present invention is preparedby suspending a specific component that is either7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one(Compound (I)) or a salt thereof in water and further adding a specificparticle binder, primary particles of Compound (I) or a salt thereof canadvantageously form secondary particles, and the preparation canadvantageously contain in a stable manner secondary particles ofCompound (I) or a salt thereof having such a mean secondary particlediameter. The specific particle binder as used herein means a componentthat can aggregate particles (primary particles) of Compound (I) or asalt thereof to form secondary particles.

In general, when a poorly water-soluble compound is suspended in waterand left for a long period of time, particles of the compound oftenprecipitate and solidify firmly (specifically, form a hard cake). Oncesuch a hard cake has been formed in an injectable preparation preparedby suspending a poorly water-soluble active ingredient in water,resuspending the active ingredient is difficult. If the activeingredient cannot be suspended, problems such as inability to inject asufficient amount of the active ingredient and undesirably loweredsyringability arise. Therefore, preventing hard cake formation is animportant issue in injectable preparations.

As explained in detail below, the injectable preparation of the presentinvention does not form a hard cake, even when Compound (I) or a saltthereof precipitates. By using a simple operation such as gentlestirring, the particles are easily resuspended advantageously. Althougha restrictive interpretation is not desired, the advantageous effect ofthe injectable preparation of the present invention is presumablyprovided based on the following mechanism. Because the injectablepreparation of the present invention is prepared by suspending aspecific component that is either7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-oneor a salt thereof in water and further adding a specific particlebinder, particles of Compound (I) or a salt thereof aggregate to formsecondary particles; therefore, even if Compound (I) or a salt thereofprecipitates, it is difficult for the particles to be in a very closelypacked state. The present invention includes injectable preparationscomprising second particles of Compound (I) or a salt thereof in aprecipitated state.

The secondary particles of Compound (I) or a salt thereof having themean secondary particle diameter mentioned above can be produced, forexample, by dispersing Compound (I) or a salt thereof having a meanprimary particle diameter of about 0.1 to 20 μm, more preferably about 1to 10 μm, and even more preferably about 2 to 5 μm, together with avehicle as described below, in water for injection. When a bulk powderof Compound (i) or a salt thereof having the above mean primary particlediameter and a specific particle binder are used and formulated into anaqueous suspension (an injectable preparation), the particles aggregateto the desired mean particle diameter, and the aggregated secondaryparticles of Compound (I) or a salt thereof can be well dispersed.

The term “mean particle diameter” as used herein refers to volume meandiameter as measured by using a laser diffraction-scattering method.Particle size distribution is measured by using a laserdiffraction-scattering method, and the mean particle diameter iscalculated from the particle size distribution.

Stated more specifically, the term “mean primary particle diameter”refers to a volume mean diameter value calculated from the particle sizedistribution measured by using a laser diffraction scattering methodwhile circulating an aqueous suspension under ultrasonic irradiationusing a circulation cell and using water as a medium. The term“secondary particle diameter” as used herein refers to a volume meandiameter value calculated from the particle size distribution measuredby using a laser diffraction scattering method while circulating theaqueous suspension using a circulation cell and using water as a medium(without ultrasonic irradiation).

Examples of particle binders that can be used in the present inventioninclude aqueous particle binders such as sodium chloride,polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, blockcopolymers of ethylene oxide and propylene oxide; and oily particlebinders such as tocopherol, tocotrienol and esters thereof, tocopherolacetate, tocopherol succinate, benzyl alcohol, poorly water-solublepolyoxyethylene diol dibenzoate, poorly water-soluble polyoxyethylenediol dimethylsulfonic acid and esters thereof, benzyl benzoate, and likebenzoic acid esters.

“Fatty acids” of polyoxyethylene sorbitan fatty acid esters arepreferably fatty acids having 12 to 18 carbon atoms, and more preferablyhaving 16 to 18 carbon atoms. Specific examples include lauric acid,myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid,and the like. Oleic acid is particularly preferable. Amongpolyoxyethylene sorbitan fatty acid esters, polyoxyethylene (20)sorbitan laurate, polyoxyethylene (20) sorbitan stearate, andpolyoxyethylene (20) sorbitan oleate are preferable. Specific examplesinclude Polysorbate 20, Polysorbate 60, and Polysorbate 80.Polyoxyethylene (20) sorbitan oleate is particularly preferable.

The polyethylene glycol preferably has an average molecular weight ofabout 200 to 6,000. Specific examples of such polyethylene glycolsinclude macrogol 400, macrogol 4000, and the like.

The block copolymer of ethylene oxide and propylene oxide (also referredto as EO/PO block random copolymer) preferably contains ethylene oxideat a higher polymerization weight ratio relative to propylene oxide. Inparticular, polyoxyethylene (160) polyoxypropylene (30) glycols (such asPluronic F68) are preferable. Such particle binders may be used singlyor in a combination of two or more. When two or more types of bindersare used, either two or more types of binders selected from aqueousparticle binders or two or more types of binders selected from oilyparticle binders are preferably used. It is preferable to use eitheraqueous particle binders alone or oily particle binders alone.

In particular, it is preferable to use at least one particle binderselected from the group consisting of sodium chloride, polyoxyethylenesorbitan fatty acid esters (in particular, polyoxyethylene (20) sorbitanoleate), polyethylene glycols, block copolymers of ethylene oxide andpropylene oxide (in particular, polyoxyethylene (160) polyoxypropylene(30) glycol), benzyl alcohol, and benzyl benzoate. More preferable isthe use of at least sodium chloride, polyoxyethylene (20) sorbitanoleate, polyethylene glycols having an average molecular weight of 200to 6,000, polyoxyethylene (160) polyoxypropylene (30) glycol, or benzylbenzoate.

Among these, sodium chloride can particularly advantageously aggregateCompound (I) or a salt thereof to a secondary particle diameter, and canstably maintain secondary particles. Further, sodium chloride canfunction as an isotonizing agent as described below. Therefore, the useof sodium chloride is particularly preferable.

Further, polyoxyethylene sorbitan fatty acid esters, polyethyleneglycols, and block copolymers of ethylene oxide and propylene oxide arepreferable because these compounds have an effect of improvingsyringability of the injectable preparation.

The concentration of the specific particle binder used in the presentinvention may vary depending on the type of particle binder used. Forexample, the particle binder is preferably contained in the injectablepreparation in a concentration of about 0.01 to 500 mg/mL, morepreferably about 0.05 to 450 mg/mL, and even more preferably about 0.06to 300 mg/mL. The particle binder is preferably contained in an amountof about 0.01 to 500 parts by weight, more preferably about 0.05 to 450parts by weight, and even more preferably about 0.06 to 300 parts byweight, per 100 parts by weight of Compound (I) or a salt thereof.

The concentration of each component that can be used as a particlebinder in the injectable preparation is described below.

Sodium chloride is preferably contained in the injectable preparation ina concentration of about 0.1 mg/mL or more, and more preferably 1 mg/lor more. More specifically, sodium chloride is preferably contained in aconcentration of about 0.1 to 400 mg/mL, more preferably about 1 to 200mg/mL, still more preferably about 1 to 100 mg/mL, and still even morepreferably about 1 to 50 mg/mL, and particularly preferably about 2 to40 mg/L. The amount of sodium chloride is preferably 1 to 100 parts byweight, more preferably 1 to 200 parts by weight, still more preferably1 to 100 parts by weight, and still even more preferably 1 to 50 partsby weight, and particularly preferably 2 to 40 parts by weight, per 100parts by weight of Compound (I) or a salt thereof.

Polyethylene glycol is preferably contained in the injectablepreparation in a concentration of about 1 to 40 mg/mL, more preferablyabout 5 to 40 mg/mL, still preferably about 1.0 to 40 mg/mL, and yetpreferably about 20 to 40 mg/mL. The amount of polyethylene glycol ispreferably 1 to 40 parts by weight, more preferably 5 to 40 parts byweight, still more preferably 10 to 40 parts by weight, and yetpreferably 20 to 40 parts by weight, per 100 parts by weight of Compound(I) or a salt thereof.

Polyoxyethylene sorbitan fatty acid ester is preferably contained in theinjectable preparation in a concentration of about 0.01 to 10 mg/mL,more preferably about 0.1 to 5 mg/mL, still preferably about 0.1 to 1mg/mL, and yet preferably about 0.2 to 0.5 mg/mL. The amount ofpolyoxyethylene sorbitan fatty acid ester is preferably 0.01 to 10 partsby weight, more preferably 0.1 to 5 parts by weight, still preferably0.1 to 1 parts by weight, and yet preferably 0.2 to 0.5 part by weight,per 100 parts by weight of Compound (I) or a salt thereof.

Benzyl benzoate is preferably contained in the injectable preparation ina concentration of about 0.1 to 10 mg/mL, more preferably about 0.5 to 5mg/mL, and still preferably about 0.5 to 3 mg/mL. The amount of benzylbenzoate is preferably 0.1 to 10 parts by weight, more preferably 0.5 to5 parts by weight, and still preferably 0.5 to 3 parts by weight, per100 parts by weight of Compound (I) or a salt thereof.

The term “100 parts by weight of Compound (I) or a salt thereof” as usedherein refers to an amount of 100 parts by weight in terms of Compound(I), which is obtained by converting the amount of Compound (I) or asalt thereof contained in the injectable preparation to the amount ofCompound (I).

The salt of Compound (I) is not particularly limited insofar as it is apharmaceutically acceptable salt. Examples include alkali metal salts(e.g., sodium salts and potassium salts); alkaline earth metal salts(e.g., calcium salts and magnesium salts) and like metal salts; ammoniumsalts; alkali metal carbonates (e.g., lithium carbonate, potassiumcarbonate, sodium carbonate, and cesium carbonate); alkali metalhydrogen carbonates (e.g., lithium hydrogen carbonate, sodium hydrogencarbonate, and potassium hydrogen carbonate); alkali metal hydroxides(e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, andcesium hydroxide), and like salts of inorganic bases; tri(lower)alkylamines (e.g., trimethylamine, triethylamine, andN-ethyldiisopropylamine), pyridine, quinoline, piperidine, imidazole,picoline, dimethylaminopyridine, dimethylaniline,N-(lower)alkyl-morpholines (e.g., N-methylmorpholine),1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7(DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), and like salts of organicbases; hydrochloride, hydrobromate, hydroiodide, sulfate, nitrate,phosphate, and like salts of inorganic acids; and formate, acetate,propionate, oxalate, malonate, succinate, fumarate, maleate, lactate,malate, citrate, tartrate, carbonate, picrate, methanesulfonate,ethanesulfonate, p-toluenesulfonate, glutamate, pamoate, and like saltsof organic acids. The term “(lower) alkyl” as used herein refers to analkyl having 3 to 6 carbon atoms.

“Compound (I) or a salt thereof” includes an anhydride of Compound (I)or of a salt thereof, a solvate (e.g., a hydrate, preferably adihydrate) of Compound (I) or of a salt thereof, various crystallineforms of such anhydrides and solvates, and mixtures thereof, unlessotherwise specified. “Compound (I) or a salt thereof” is preferably ananhydride of Compound (I) or of a salt thereof, or a hydrate of Compound(I) or of a salt thereof, more preferably a hydrate of Compound (I) orof a salt thereof, and even more preferably a dihydrate of Compound (I)or of a salt thereof. The phrase “an anhydride of Compound (I) or of asalt thereof” means an anhydride of Compound (I) or an anhydride of asalt of Compound (I). The phrase “a solvate (e.g., a hydrate) ofCompound (I) or of a salt thereof” means a solvate (e.g., a hydrate) ofCompound (I) or a solvate (e.g., a hydrate) of a salt of Compound (I).

Compound (I) or a salt thereof can be used singly or in a combination oftwo or more (for example, as a mixture).

An anhydride of Compound (I) or of a salt thereof can be obtained, forexample, by using the methods disclosed in Examples 1 and 42 to 47 ofJP2006-316052A, the disclosure of which is incorporated herein byreference. A preferable example of a hydrate of Compound (I) or of asalt thereof is a dihydrate as described above. The dihydrate can beobtained, for example, by using a method comprising the steps of:

(1) mixing an acid (preferably at least one organic acid selected fromthe group consisting of acetic acid and lactic acid) and Compound (I) inan alcohol-water mixed solution (preferably a mixture of ethanol andwater) to prepare an acidic mixed solution;(2) cooling the solution obtained in the above step; and(3) mixing the solution cooled in step (2) with an alkali (such assodium hydroxide or potassium hydroxide) to adjust the pH to 7 or more.More specifically, the dihydrate of Compound (I) can be produced, forexample, by using the following production method (A) or (B).

Production method (A) comprises the steps of:

(a1): mixing acetic acid and Compound (I) in an ethanol-water mixedsolution to prepare an acidic solution;(a2): cooling the solution obtained in step (a1) to 4° C. or lower; and(a3): adjusting the cooled solution to a pH of 7 or more with an alkali,such as sodium hydroxide or potassium hydroxide.

Production method (B) comprises the steps of:

(b1): mixing lactic acid and Compound (I) in an ethanol-water mixedsolution to prepare an acidic mixed solution;(b2): cooling the solution obtained in step (b1) to 4° C. or lower; and(b3): adjusting the cooled solution to a pH of 7 or more with an alkalisuch as sodium hydroxide or potassium hydroxide.

The dihydrate of the benzothiophene compound of Formula (I) or of a saltthereof can be produced by using steps (1) to (3) described above. Step(1) may be a step (step (I′)) in which an alcohol, water, at least oneorganic acid selected from the group consisting of acetic acid andlactic acid, and Compound (I) are mixed to prepare an acidic mixedsolution. Particularly preferably, in step (1), at least one organicacid selected from the group consisting of acetic acid and lactic acidand an anhydride of the benzothiophene compound of Formula (I) are mixedin an ethanol-water mixed solution to prepare an acid solution. Lacticacid that is used as the organic acid may be D-form, L-form, or amixture thereof.

The ethanol-water mixed solution used in step (1) is preferably preparedso as to contain ethanol in an amount of about 95 volume % or less, morepreferably about 70 volume % or less, and even more preferably about 60volume % or less. When the solution contains ethanol in an amount of 95volume % or less, a dihydrate of Compound (I) can be obtained. Althoughthe lower limit of the amount of ethanol in the solution is notparticularly limited, it is preferably about 20 volume %, and morepreferably about 30 volume %.

The concentration of the benzothiophene compound of Formula (I) in theethanol-water mixed solution is preferably about 0.1 to 30 wt %, morepreferably about 0.5 to 20 wt %, and even more preferably about 1 to 10wt %. The expression “wt %” used herein refers to w/w %. When theconcentration of the benzothiophene compound of Formula (I) is set tothe above range, the benzothiophene compound of Formula (I) can be fullydissolved in the ethanol-water mixed solution, and a dihydrate with ahigher purity can be obtained by performing the subsequent stepsdescribed below (steps (2) and (3)).

The amount of the organic acid in the ethanol-water mixed solution isnot particularly limited insofar as the system can be adjusted to anacidic condition. For example, the organic acid is preferably containedin an amount of about 0.1 to 20 wt %, more preferably about 0.3 to 10 wt%, and even more preferably about 0.5 to 5 wt %, in the ethanol-watermixed solution.

The amount of the organic acid is not particularly limited insofar asthe system can be adjusted to an acidic condition. For example, theorganic acid is preferably contained in an amount of about 5 to 100parts by weight, and more preferably about 20 to 80 parts by weight,based on 100 parts by weight of the benzothiophene compound of Formula(I).

The temperature at which the solution is prepared in step (1) is notparticularly limited insofar as the following conditions are met: thebenzothiophene compound of Formula (I) is dissolved in a liquidcontaining the above organic acid and ethanol-water mixed solution;ethanol, water, or the organic acid does not vaporize; and thebenzothiophene compound of Formula (i) does not decompose. Specifically,the temperature is preferably about 50 to 120° C., and more preferablyabout 70 to 100° C. A reflux temperature (about 80° C.) may be used.Step (2) is a step in which the solution obtained in step (1) is cooled.

The cooling temperature is 5° C. or less, preferably about 0° C. orless, and more preferably about −2° C. or less. When the pH of thesolution is adjusted with an alkali in the subsequent step, heat isgenerated. Therefore, when the cooling temperature is higher than 5° C.,the yield of the dihydrate of the benzothiophene compound of Formula (I)or of a salt thereof tends to be insufficient. The lower limit of thecooling temperature in step (2) is not particularly limited. However, inview of the fact that the temperature must be raised in the subsequentstep and that water may be frozen, the lower limit of the coolingtemperature is preferably about −20° C., and more preferably about −10°C.

Step (3) is a step in which the solution cooled in step (2) is mixedwith an alkali to adjust the pH to 7 or more. Examples of the alkaliinclude sodium hydroxide, potassium hydroxide, and the like.

For mixing the solution cooled in step (2) with an alkali, an aqueousalkali solution prepared in advance may be used. The concentration ofthe aqueous alkali solution is, for example, about 0.1 to 25 wt %, andmore preferably about 0.5 to 10 wt %.

To avoid a rapid temperature rise of the mixed solution in the system bythe addition of an alkali (aqueous solution) as described above, thealkali (aqueous solution) is preferably pre-cooled. The temperature ofthe alkali (aqueous solution) is preferably about −5 to 15° C., and morepreferably about −2 to 5° C.

The amount of alkali is not particularly limited insofar as the solutionin the system can be adjusted to a pH of 7 or more. For example, analkali is preferably added in an amount of about 0.3 to 10 parts byweight, and more preferably about 0.5 to 3 parts by weight, per part byweight of the organic acid incorporated in the solution in step (1).

In step (3), the solution is adjusted with an alkali to a pH of 7 ormore, more preferably about 7.5 or more, and more preferably about 8 ormore. When the pH is less than 7, the yield of the dihydrate of thebenzothiophene compound of Formula (I) or of a salt thereof tends to beinsufficient. Although the upper limit of the pH is not particularlylimited, it is preferably, for example, a pH of about 1.2, and morepreferably a pH of about 10, in view of facilitating washing theprecipitated dihydrate of the benzothiophene compound of Formula (I),forming a salt of the benzothiophene compound, etc.

By performing steps (1) to (3), the dihydrate of the benzothiophenecompound of Formula (I) or of a salt thereof is precipitated.

The precipitated dihydrate of the benzothiophene compound of Formula (I)or of a salt thereof is separated into solid and liquid phases by usinga known method and purified by washing with water.

Preferably, the obtained dihydrate of the benzothiophene compound ofFormula (I) is heated to about 10° C. or higher, and more preferably toabout 10 to 50° C.

The physicochemical properties of the dihydrate of the benzothiophenecompound of Formula (I) obtained by using the above production processare shown below.

X-Ray Powder Diffraction

The dihydrate of the benzothiophene compound of Formula (I) isidentified by using an X-ray powder diffraction pattern measured bycopper radiation of λ=1.5418 Å through a monochromator. The dihydrate ofthe benzothiophene compound of Formula (I) has peaks shown in FIG. 2 inthe X-ray powder diffraction pattern, and has characteristic peaks atthe following diffraction angles (2θ) in the X-ray powder diffractionpattern. These peaks are different from the peaks of the knownbenzothiophene compound of Formula (I) (in the form of an anhydride).

Diffraction Angles (2θ)

8.1°

8.9°

15.1°

15.6°

24.4°

The dihydrate of the benzothiophene compound of Formula (I) of thepresent invention has peaks at the following diffraction angles (2θ) asshown in FIG. 2, in addition to the above peaks.

Diffraction Angles (2θ)

11.6°, 12.2°, 14.0°, 16.3°, 18.1°, 18.4°, 18.9°, 19.5°, 20.5°, 21.5°,22.6°, 23.3°, 25.0°, 26.1°, 26.4°, 27.1°, 28.1°, 28.5°, 28.9°, 29.8°,30.4°, 30.7°, 31.6°, 32.9°, 33.9°, 34.4°, 35.2°, 36.0°, 36.7°, 37.4°,38.3°.

Although the above diffraction angles (2θ) may contain an error of −0.2to +0.2° according to the measuring instrument, measurement conditions,etc., such a level of error is within an acceptable range in the presentinvention.

Infrared Absorption Measurement

The dihydrate of the benzothiophene compound of Formula (I) isidentified by using an infrared absorption spectrum measured by usingthe potassium bromide tablet method. In the infrared absorptionspectrum, the dihydrate of the benzothiophene compound of Formula (I)has a spectrum as shown in FIG. 3 and has peaks at the followingwavenumbers (cm⁻¹):

Wavenumbers

3509 cm⁻¹

2934 cm⁻¹

2812 cm⁻¹

1651 cm⁻¹

1626 cm⁻¹

1447 cm⁻¹

1223 cm⁻¹

839 cm⁻¹

The dihydrate of the benzothiophene compound of Formula (I) of thepresent invention has peaks at the wavenumbers shown in FIG. 3, inaddition to the above peaks.

Although the wavenumbers (cm⁻¹) may contain an error of −0.5 to +0.5cm⁻¹ according to the measuring instrument, measurement conditions,etc., such a level of error is within an acceptable range in the presentinvention.

The dihydrate of the benzothiophene compound of Formula (I) isidentified by using a Raman spectrum. The dihydrate has the Ramanspectrum shown in FIG. 4 and has peaks in the vicinity of the followingwavenumbers (cm⁻¹):

Wavenumbers

1497 cm⁻¹

1376 cm⁻¹

1323 cm⁻¹

1311 cm⁻¹

1287 cm⁻¹

1223 cm⁻¹

781 cm⁻¹

The dihydrate has peaks in the vicinity of the following wavenumbersshown in FIG. 4, in addition to the above peaks:

Wavenumbers

1656 cm⁻¹, 1613 cm⁻¹, 1563 cm⁻¹, 1512 cm⁻¹, 1468 cm⁻¹, 1446 cm⁻¹, 1241cm⁻¹, 1203 cm⁻¹, 1145 cm⁻¹, 1096 cm⁻¹, 1070 cm⁻¹, 971 cm⁻¹, 822 cm⁻¹

Water Content

The dihydrate of the benzothiophene compound of Formula (I) containswater in an amount of 6.5 to 8.8 wt %, and more specifically 7.3 to 8.1wt %. The water content is measured by using the Karl Fischer method.

¹H-NMR Measurement

The dihydrate of the benzothiophene compound of Formula (I) isidentified according to peaks measured by 1H-NMR spectroscopy. Thedihydrate of the benzothiophene compound of Formula (I) has a ¹H-NMRspectrum as shown in FIG. 1 and has proton peaks in the ¹H-NMR spectrummeasured in Example 1 below.

The injectable preparation preferably contains Compound (I) or a saltthereof in a proportion of about 0.1 to 40 wt %, more preferably about 1to 20 wt %, and even more preferably about 5 to 15 wt %, based on thetotal weight of the injectable preparation. That is, Compound (I) or asalt thereof is preferably present in the injectable preparation in anamount of about 0.1 to 40% (w/v), more preferably about 1 to 20% (w/v),even more preferably about 2 to 15% (w/v), still more preferably about 5to 15% (w/v), and particularly preferably about 5 to 11% (w/v), based onthe total weight of the injectable preparation. More specifically, theinjectable preparation preferably contains Compound (I) or a saltthereof in a concentration of, for example, about 1 to 400 mg/mL, morepreferably about 10 to 200 mg/mL, even more preferably about 20 to 150mg/mL, and still more preferably about 50 to 110 mg/mL.

The proportion and amount of Compound (I) or a salt thereof in theinjectable preparation of the present invention are based on theproportion and amount of Compound (I).

In the production of an injectable preparation of the present inventionthat contains Compound (I) or a salt thereof in a relatively highconcentration (specifically, 200 mg/mL or higher), it may be difficultto handle the injectable preparation because of its high viscosity(increased viscosity due to air bubble entrapment). In such a case, adefoaming step is preferably added to the production process. It is alsopreferable to use a suspending agent that suppresses viscosity, or,further, to use a water-repellent vial (in particular, a fluorine-coatedwater-repellent vial). Use of a water-repellent vial can enhancehandling ease and reduce foaming.

The amount of Compound (I) or a salt thereof in the injectablepreparation is preferably about 1 to 400 mg, more preferably about 10 to200 mg, and even more preferably about 50 to 110 mg.

The bulk powder of Compound (I) or a salt thereof having the desiredprimary particle mean particle diameter can be produced by using a wetmilling process, such as wet ball milling using media or wet millingwithout using media (e.g., a Manton-Gaulin homogenizer), or by using adry milling process, such as jet milling. A freeze grinding method inliquid nitrogen or under freezing can also be used.

The wet milling process preferably uses wet ball milling. When thedesired mean particle diameter of the primary particles of Compound (I)or a salt thereof is more than about 1 m, the primary suspension(comprising a mixture of Compound (I) or a salt thereof with a vehicle)is passed through a wet ball mill a single time (single pass) at about 5to 15 L/hr, preferably about 8 to 12 L/hr, and more preferably about 10L/hr, to reduce the mean particle diameter of the primary particles tothe desired range of, for example, about 1 to 5 μm.

In addition to ball mills (such as Dyno mills), other low-energy mills(such as roller mills) and high-energy mills may be used. Examples ofusable high-energy mills include Netzsch mills, DC mills, and Planetarymills.

Other techniques for particle size reduction that may be used includeaseptic controlled crystallization, high-shear homogenization,high-pressure homogenization, and microfluidization.

The injectable preparation of the present invention can stably containsecondary particles of Compound (I) or a salt thereof having thespecific mean secondary particle diameter mentioned above.

With respect to an injectable preparation that comprises Compound (I) ora salt thereof as an active ingredient, the injectable preparationcontaining this active ingredient in the form of secondary particleshaving the specific secondary particle diameter mentioned above exhibitsbetter sustained release properties (more specifically, excessiveincrease of blood concentration is not observed and the sustainabilityof the medicinal efficacy is equal or better) after administration,compared to an injectable preparation containing the same activeingredient in the form of primary particles.

Furthermore, the injectable preparation of the present inventioncomprising secondary particles of Compound (I) or a salt thereof havingthe specific mean secondary particle diameter mentioned above has thefollowing property: when allowed to stand for a long period of time, thesecondary particles precipitate but the precipitate does not solidify,and upon a simple operation such as gentle stirring or slight shakingwith the hand, the secondary particles are easily suspended and revertto a suspension. Therefore, the injectable preparation of the presentinvention can be easily restored to a suspension from the precipitatethat is formed after long-term storage, and the restored suspension asis can be preferably injected into a patient.

When precipitation occurs after being allowed to stand, theprecipitation height (Rf value) is preferably 0.5 or more, morepreferably 0.6 or more, still preferably 0.7 or more, and yet preferably0.8 or more, with the height of the liquid surface defined as 1. The Rfvalue is measured after the injectable preparation is stirred well andallowed to stand at room temperature for at least five days. A larger Rfvalue is considered to indicate greater difficulty for the precipitatedparticles to be in a very closely packed state. Accordingly, apharmaceutical preparation with a larger Rf value is most likely to havea high effect of preventing hard cake formation.

The injectable preparation of the present invention preferably has arelative osmotic pressure close to 1. More specifically, the injectablepreparation preferably has a relative osmotic pressure of 1 to 2, morepreferably 1 to 1.5, even more preferably 1 to 1.2, and still even morepreferably 1 to 1.1.

The injectable preparation containing Compound (I) of the presentinvention or a salt thereof preferably comprises, in addition toCompound (I) or a salt thereof, a vehicle for Compound (I) or a saltthereof, and water for injection.

Examples of the vehicle for Compound (I) or a salt thereof includeparticle binders, dispersants (suspending agents), isotonizing agents,stabilizers, buffers, pH adjusters, solvents, and the like. Inparticular, as stated above, due to the specific particle bindercontained in the injectable preparation of the present invention,Compound (I) or a salt thereof aggregates to form secondary particles,and the injectable preparation can advantageously contain the secondaryparticles in a stable manner. Therefore, the use of a specific particlebinder is important. Other vehicles can be suitably added insofar as theeffect of the present invention is not adversely affected.

Examples of dispersants (suspending agents) include sodium carboxymethylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose,hydroxypropyl ethylcellulose, hydroxypropyl methylcellulose, andCarbopol 934 (registered trademark) (manufactured by Union Carbide)),cetylpyridinium chloride, gelatin, casein, lecithin (phosphatide),dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid,benzalkonium chloride, calcium stearate, glyceryl monostearate,cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters,polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol1000), polyoxyethylene castor oil derivatives, dodecyl trimethylammonium bromide, polyoxyethylene stearate, colloidal silicon dioxide,phosphate, sodium dodecyl sulfate, carboxymethylcellulose calcium,hydroxypropyl celluloses (e.g., HPC, HPC-SL, and HPC-L),methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose phthalate, non-crystalline cellulose,aluminum magnesium silicate, triethanolamine, polyvinyl alcohol (PVA),4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide andformaldehyde (also known as tyloxapol, superione, and triton);tetrafunctional block copolymers derived from sequential addition ofpropylene oxide and ethylene oxide to ethylenediamine (poloxamines)(e.g., Tetronic 908 (registered trademark), also known as Poloxamine 908(registered trademark) (manufactured by BASF Wyandotte Corporation,Parsippany, N.J.)); charged phospholipids such as dimyristoylphosphatidyl glycerol, dioctylsulfosuccinate (DOSS); Tetronic 1508(registered trademark) (T-1508) (manufactured by BASF WyandotteCorporation), dialkylesters of sodium sulfosuccinic acid (e.g., AerosolOT (registered trademark), which is a dioctyl ester of sodiumsulfosuccinic acid (manufactured by American Cyanamid)); Duponol P(registered trademark), which is sodium lauryl sulfate (manufactured byDuPont); Triton X-200 (registered trademark), which is an alkyl arylpolyether sulfonate (manufactured by Rohm and Haas); Crodestas F-110(registered trademark), which is a mixture of sucrose stearate andsucrose distearate (manufactured by Croda Inc.);p-isononylphenoxypoly-(glycidol), also known as Olin-10G (registeredtrademark) or Surfactant 10-G (registered trademark) (manufactured byOlin Chemicals, Stamford, Conn.); Crodestas SL-40 (manufactured byCroda, Inc.); and SA9OHCO, which is C₁₈H₃₇CH₂ (CON(CH₃))—CH₂(CHOH)₄(CH₂OH)₂ (manufactured by Eastman Kodak Co.);decanoyl-N-methylglucamide; n-decyl-β-D-glucopyranoside;n-decyl-β-D-maitopyranoside; n-dodecyl-β-D-glucopyranoside;n-dodecyl-β-D-maltoside; heptanoyl-N-methylglucamide;n-heptyl-β-D-glucopyranoside; n-heptyl-β-D-thioglucoside;n-hexyl-β-D-glucopyranoside; nonanoyl-N-methylglucamide;n-nonyl-β-D-glucopyranoside; octanoyl-N-methylglucamide;n-octyl-β-D-glucopyranoside; octyl-β-D-thioglucopyranoside, methionine(which may be in any of D-form, L-form, and racemic form (DL form)), gumarabic, polyvinylpyrrolidone, and the like. Such dispersants can be usedsingly or in a combination of two or more.

Most of these dispersants are known pharmaceutical excipients and aredescribed in detail in the Handbook of Pharmaceutical Excipients,published jointly by the American Pharmaceutical Association and thePharmaceutical Society of Great Britain (The Pharmaceutical Press,1986). Pharmaceutical excipients described in this publication can alsobe used. Commercially available dispersants may be used, or dispersantscan be prepared by using techniques known in the art.

The concentration of the dispersant in the injectable preparation ispreferably about 0.1 to 45 mg/mL, more preferably about 0.5 to 40 mg/mL,and even more preferably about 0.6 to 35 mg/mL, based on the totalvolume of the injectable preparation. The proportion of the dispersantin the injectable preparation is preferably about 0.01 to 10 wt %, morepreferably about 0.05 to 8 wt %, and even more preferably about 0.06 to5 wt %. The amount of the dispersant is preferably about 0.01 to 45parts by weight, more preferably about 0.1 to 40 parts by weight, andeven more preferably about 0.5 to 35 parts by weight, based on 100 partsby weight of Compound (I) or a salt thereof.

Dispersants may also have functions as other additives. In this case,the concentration, proportion, and amount of dispersant are the total ofthe concentrations, proportions, and amounts of such additives used.

Examples of isotonizing agents include non-electrolytic osmoticmodulating agents, such as mannitol, sucrose, maltose, xylitol, glucose,starch, sorbitol, glycerol, and propylene glycol; and electrolyticosmotic modulating agents, such as sodium chloride, potassium chloride,sodium sulfate, and magnesium chloride. Such isotonizing agents can beused singly or in a combination of two or more.

When an oily particle binder is used as the particle binder, sorbitol ispreferably used. When an aqueous particle binder is used as the binder,sodium chloride is preferably used.

Sugars or sugar alcohols, such as mannitol, trehalose, sucrose, maltose,xylitol, and sorbitol, are preferable because they can be expected tostabilize the produced injectable preparation during frozen storage.

The concentration of the isotonizing agent in the injectable preparationis preferably about 0.1 to 70 mg/mL, more preferably about 0.5 to 60mg/mL, and even more preferably about 1 to 55 mg/mL. The proportion ofthe isotonizing agent in the injectable preparation is preferably about0.05 to 10 wt %, more preferably about 0.1 to 7 wt %, and even morepreferably about 0.2 to 5 wt %. The amount of the isotonizing agent ispreferably about 1 to 70 parts by weight, more preferably about 2 to 60parts by weight, and even more preferably about 4 to 55 parts by weight,based on 100 parts by weight of Compound (I) or a salt thereof.

Isotonizing agents may also have functions as other additives. In thiscase, the concentration, proportion, and amount of isotonizing agent arethe total of the concentrations, proportions, and amounts of suchadditives used.

Examples of stabilizers include ascorbic acid, ascorbic acid derivatives(such as erythorbic acid, and sodium ascorbate), methionine, and thelike. The methionine may be in any of D form, L form, and racemic form(DL form).

The concentration of the stabilizer in the injectable preparation ispreferably about 0.1 to 5 mg/mL, more preferably about 0.5 to 4 mg/mL,and even more preferably about 1 to 3 mg/mL. The proportion of thestabilizer in the injectable preparation is preferably about 0.01 to 5wt %, more preferably about 0.05 to 2 wt %, and even more preferablyabout 0.1 to 0.5 wt %. The amount of the stabilizer is preferably about0.1 to 5 parts by weight, more preferably about 0.5 to 4 parts byweight, and even more preferably about 0.1 to 3 parts by weight, basedon 100 parts by weight of Compound (I) or a salt thereof.

Stabilizers may also have functions as other additives. In this case,the concentration, proportion, and amount of stabilizer are the total ofthe concentrations, proportions, and amounts of such additives used.

Examples of buffers include sodium phosphate, potassium phosphate, trisbuffers, sodium hydrogenphosphate, sodium dihydrogenphosphate, trisodiumphosphate, and hydrates thereof. Specific examples of hydrates includesodium dihydrogenphosphate dihydrate and disodium hydrogenphosphatedodecahydrate. Such buffers may be used singly or in a combination oftwo or more.

The proportion and amount of the buffer are such that the injectablepreparation containing Compound (I) or a salt thereof can be adjusted toa pH described below (preferably a pH of about 4 to 9, more preferablyabout 4.5 to 8.5, and even more preferably about 5 to 8). Generally, theproportion of the buffer in the injectable preparation may suitablychange according to the type of buffer, etc. For example, it ispreferably about 0.01 to 10 mg/mL, more preferably about 0.1 to 7 mg/mL,and even more preferably about 0.2 to 5 mg/mL, based on the total weightof the injectable preparation. The concentration of the buffer in theinjectable preparation is preferably about 0.001 to 5 wt %, morepreferably about 0.01 to 1 wt %, and even more preferably about 0.02 to0.8 wt %. The amount of the buffer in the injectable preparation mayalso suitably change according to the type of buffer, etc. For example,the amount of the buffer is preferably about 0.01 to 10 parts by weight,more preferably about 0.1 to 5 parts by weight, and even more preferablyabout 0.2 to 3 parts by weight, based on 100 parts by weight of Compound(I) or a salt thereof.

When the injectable preparation has a high pH and is adjusted to a lowerpH, an acidic pH adjuster, such as hydrochloric acid, acetic acid, orcitric acid, can be used.

When the injectable preparation has a low pH and is adjusted to a higherpH, a basic pH adjuster, such as sodium hydroxide, potassium hydroxide,calcium carbonate, magnesium oxide, or magnesium hydroxide, can be used.Sodium hydroxide is preferably used.

Such pH adjusters may be used singly or in a combination of two or more.

The proportion and amount of the pH adjuster are such that theinjectable preparation containing Compound (I) or a salt thereof can beadjusted to a pH described below (preferably a pH of about 4 to 9, morepreferably about 4.5 to 8.5, and even more preferably about 5 to 8). Toachieve the desired pH, an acid or a base is suitably selected.

A suspension is obtained by suspending Compound (I) or a salt thereof,and a vehicle for Compound (I) or a salt thereof in water for injection.Although there is no particular limitation, it is preferable that thevehicle is dissolved in water for injection to prepare an injectablesolution and Compound (I) or a salt thereof is suspended in theinjectable solution.

Sterilized water (pure water) is used as the water for injection. Theamount of water for injection is preferably about 0.7 to 1.0 mL, andmore preferably about 0.8 to 0.9 mL, per mL of the injectablepreparation.

According to the injectable preparation of the present invention, thesuspension as is can be used as an injectable preparation.

The obtained injectable preparation preferably has a pH of about 4 to 9,more preferably about 4.5 to 8.5, and even more preferably about 5 to 8.When the pH is set to about 5 or more, a stable suspension in which asmaller amount of a drug is dissolved in an injection solvent can bepreferably prepared. When the pH is set to about 8 or less, a stablesuspension by which stimulation is reduced can be preferably prepared.

Compound (I) or a salt thereof, and a vehicle for Compound (I) or a saltthereof used in the injectable preparation of the present invention maybe a freeze-dried product or a powder mixture. Such a freeze-driedproduct can be obtained, for example, by suspending Compound (I) or asalt thereof and a vehicle for Compound (I) or a salt thereof in water,and then freeze-drying the suspension. The proportions of Compound (I)or a salt thereof, and a vehicle for Compound (I) or a salt thereof inthe freeze-dried product or powder mixture can be suitably set to theabove proportions by subsequent addition of water for injection.

The freeze-dried product or powder mixture may also be formulated intoan injectable preparation by the addition of water for injection at thetime of use.

The method for producing the injectable preparation of the presentinvention is not particularly limited. For example, when an aqueousparticle binder is used as the particle binder, the injectablepreparation can be produced by using a process comprising the steps ofdissolving a vehicle in water for injection to prepare an injectablesolution and further suspending Compound (I) or a salt thereof in theobtained injectable solution.

When an oily particle binder is used as the particle binder, theinjectable preparation can be produced, for example, by using a processcomprising the steps of dissolving a vehicle in water for injection andadding an oily particle binder filtered through a sterilized oleophilicfilter to obtain an injectable solution, further incorporating Compound(I) or a salt thereof in the obtained injectable solution, and stirringand heating the resulting mixture.

The injectable preparation containing Compound (I) or a salt thereofaccording to the present invention almost creates no patient complianceproblems and can be preferably administered to deliver a drug.

When the injectable preparation containing Compound (I) or a saltthereof according to the present invention is produced, it isparticularly preferable that all production steps are sterile. That is,it is preferable that a sterile Compound (I) or a salt thereof, and asterile vehicle are mixed aseptically to form a sterile suspension.

The method for obtaining a sterile bulk powder of Compound (I) or a saltthereof includes, for example, the following methods: sterilization bymeans of ionizing irradiation with an electron beam or gamma rays,aseptic crystallization, UV irradiation, autoclaving, etc.; gassterilization with ethylene oxide or hydrogen peroxide; suspendedparticle filter sterilization; and an aseptic technique within a cleanbench.

Vehicles (a particle binder, a dispersant (suspending agent), anisotonizing agent, a stabilizer, a buffer, a pH adjuster, a solvent) andwater are preferably sterilized by autoclaving, filtration, etc. afterbeing prepared.

The preparation comprising Compound (I) or a salt thereof according tothe present invention can be preferably used to treat schizophrenia andassociated disorders (such as bipolar disorder and dementia) in humanpatients. A preferable dose of the injectable preparation of the presentinvention is, for example, a single injection or multiple injections ofthe preparation containing Compound (I) or a salt thereof in aconcentration of about 50 to 150 mg per mL of the preparation, which canbe given once a month. Although the injectable preparation is preferablyadministered intramuscularly, subcutaneous injection is also acceptable.

Because the sustained release period during which Compound (I) or a saltthereof is released into the body is long, the injectable preparation ofthe present invention is useful as a depot medication (asustained-release injectable preparation). Furthermore, the injectablepreparation of the present invention is less irritating and is alsoexcellent in terms of stability. Because poor syringability results inincreased irritation, good syringability is preferable.

According to the injectable preparation of the present invention, atherapeutic amount of the above sustained-release injectable preparationcan be administered to a patient in need of treatment and can treatcentral nervous system diseases.

Specific examples of the central nervous system diseases treated by theinjectable preparation of the present invention that contains adihydrate of benzothiophene compound include schizophrenia, such astreatment-resistant, refractory and chronic schizophrenia, emotionaldisturbance, psychotic disorder, mood disorder, bipolar disorder (e.g.,bipolar I disorder and bipolar II disorder), mania, depression,endogenous depression, major depression, melancholic andtreatment-resistant depression, dysthymic disorder, cyclothymicdisorder, anxiety disorder (e.g., panic attack, panic disorder,agoraphobia, social phobia, obsessive-compulsive disorder, posttraumatic stress disorder, generalized anxiety disorder, and acutestress disorder), somatoform disorder (e.g., hysteria, somatizationdisorder, conversion disorder, pain disorder, and hypochondria),factitious disorder, dissociative disorder, sexual disorder (e.g.,sexual dysfunction, libido disorder, sexual arousal disorder, anderectile dysfunction), eating disorder (e.g., anorexia nervosa andbulimia nervosa), sleep disorder, adjustment disorder, substance-relateddisorder (e.g., alcohol abuse, alcohol intoxication and drug addiction,amphetamine addiction, and narcotism), anhedonia (e.g., iatrogenicanhedonia, anhedonia of a psychic or mental cause, anhedonia associatedwith depression, anhedonia associated with schizophrenia), delirium,cognitive impairment, cognitive impairment associated with Alzheimer'sdisease, Parkinson's disease, and other neurodegenerative diseases, BPSD(Behavioral and Psychological Symptoms of Dementia) caused by cognitiveimpairment, cognitive impairment in schizophrenia, cognitive impairmentcaused by treatment-resistant, refractory or chronic schizophrenia,vomiting, motion sickness, obesity, migraine, pain, mental retardation,autistic disorder (autism), Tourette's syndrome, tic disorder, attentiondeficit hyperactivity disorder, conduct disorder, Down's syndrome, etc.;and various other central nervous system diseases. The pharmaceuticalpreparation of the present invention is extremely effective for theamelioration of these central nervous system diseases. In particular,the pharmaceutical preparation of the present invention is effective forthe treatment or prevention of the recurrence of schizophrenia, bipolardisorder or depression.

One example of the particularly preferable particle binder of theinjectable preparation of the present invention comprises (i) sodiumchloride, and (ii) at least one member selected from the groupconsisting of polyoxyethylene sorbitan fatty acid esters, blockcopolymers of ethylene oxide and propylene oxide, and polyethyleneglycol. Here, component (ii) is preferable at least one member selectedfrom the group consisting of polyoxyethylene sorbitan fatty acid estersand polyethylene glycol. In particular, in the injectable preparationusing a dihydrate of Compound (I), use of the particle binder ispreferable.

By containing Compound (I) or a salt thereof or Compound (I) or a saltthereof and sodium chloride, Compound (I) or a salt thereof candesirably form secondary particles; however, syringability is notexcellent. Compound (ii) described above improves the syringability;therefore, (i) sodium chloride and component (ii) are preferably used incombination as a particle binder.

As described above, the injectable preparation of the present inventionis such that the secondary particles of Compound (I) or a salt thereofprecipitate when stood for a long period of time but the precipitatedoes not solidify; upon a simple operation such as gentle stirring orslightly shaking with the hand, the secondary particles are easilysuspended and revert to a suspension. Therefore, a prefilled syringeinto which the injectable preparation of the present invention is filledbeforehand is useful, in particular, in clinical practice. In otherwords, a syringe that is prefilled with the injectable preparation hasexcellent storage stability and is simple and convenient since even whenprecipitation occurs due to the prefilled syringe having stood for sometime, it easily returns to a suspension by shaking with hand, etc. Thescope of the present invention encompasses such a prefilled syringe anda kit comprising the prefilled syringe.

Effect of the Invention

The present invention provides a long-acting medication administrationform of Compound (I) or a salt thereof, which is usable as a sustainedrelease injectable preparation that releases a therapeutically effectiveamount of Compound (I) or a salt thereof over a period of at least oneweek. The injectable preparation of the present invention exhibitssuperior sustained release properties after administration compared toan injectable preparation that contains Compound (I) or a salt thereofin the form of primary particles. (More specifically, excessive increasein blood concentration is not observed and the sustainability of themedicinal efficacy is equal or better). Furthermore, even when thesecondary particles of Compound (I) or a salt thereof have precipitatedafter being allowed to stand for a long period of time, the precipitatedoes not solidify, and it easily returns to a suspension as thesecondary particles are easily suspended by a simple operation such asgentle stirring or shaking with hand. Therefore, the injectablepreparation of the present invention can be easily restored to asuspension from the precipitate that is formed after long-term storage(i.e., for five days or more), and the restored suspension as is can bepreferably injected into a patient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the ¹H-NMR spectrum of the benzothiophene compoundrepresented by Formula (I) synthesized in Production Example 1.

FIG. 2 shows the X-ray powder diffraction pattern of the dihydrate ofthe benzothiophene compound represented by Formula (I) synthesized inProduction Example 1.

FIG. 3 shows the infrared absorption spectrum of the dihydrate of thebenzothiophene compound represented by Formula (I) synthesized inProduction Example 1.

FIG. 4 shows the Raman spectrum of the dihydrate of the benzothiophenecompound represented by Formula (I) synthesized in Production Example 1.

FIG. 5 shows the ¹H-NMR spectrum of the benzothiophene compoundrepresented by Formula (I) synthesized in Production Example 2.

FIG. 6 shows the X-ray powder diffraction pattern of the dihydrate ofthe benzothiophene compound represented by Formula (I) synthesized inProduction Example 2.

FIG. 7 shows the infrared absorption spectrum of the dihydrate of thebenzothiophene compound represented by Formula (I) synthesized inProduction Example 2.

FIG. 8 shows the Raman spectrum of the dihydrate of the benzothiophenecompound represented by Formula (I) synthesized in Production Example 2.

FIG. 9 shows the Raman spectrum of the dihydrate of the benzothiophenecompound represented by Formula (I) synthesized in Production Example 3.

FIG. 10 shows the ¹H-NMR spectrum of the anhydride of the benzothiophenecompound represented by Formula (I) synthesized in Production Example 4.

FIG. 11 shows the X-ray powder diffraction pattern of the anhydride ofthe benzothiophene compound synthesized in Production Example 4.

FIG. 12 shows the infrared absorption spectrum of the anhydride of thebenzothiophene compound synthesized in Production Example 4.

FIG. 13 is a graph showing the mean blood concentration-time profilesobtained in Test Example 1 in which the injectable preparationscontaining Compound (I) of Examples 1 and 2 as an active ingredient wereadministered to rats.

FIG. 14 is a graph showing the mean blood concentration-time profilesobtained in Test Example 2 in which the injectable preparationscontaining Compound (I) of Examples 3 and 4 as an active ingredient wereadministered to rats.

FIG. 15 is a graph showing the mean blood concentration-time profilesobtained in Test Example 3 in which the injectable preparations ofExample A, Example B, Comparative Example A, and Comparative Example Bwere administered to rats.

FIG. 16 is a graph showing the mean blood concentration-time profilesobtained in Test Example 4 in which the injectable preparations ofExamples C to F were administered to rats.

FIG. 17 is a graph showing the Rf values of an injectable preparation ofeach Example measured in Test Example 5.

MODE FOR CARRYING OUT THE INVENTION Examples

The present invention is described in further detail with reference toExamples and Test Examples. However, the scope of the invention is notlimited to these Examples.

Production Example 1 Synthesis of dihydrate of Compound (I)

Methanol (149 L), 7-hydroxy-1H-quinolin-2-one (14.87 kg), and potassiumhydroxide (6.21 kg) were mixed in a reaction vessel, and the resultingmixture was stirred. After dissolution, 1-bromo-4-chlorobutane (47.46kg) was added thereto, and the resulting mixture was stirred underreflux for seven hours. Thereafter, the mixture was stirred at 10° C.for one hour. The precipitated crystal was centrifuged and washed withmethanol (15 L). The wet crystal was collected and placed in a tank.Water (149 L) was added thereto, followed by stirring at roomtemperature. After centrifugation, the result was washed with water (30L). The wet crystal was collected and placed in a tank. After addingmethanol (74 L), the mixture was stirred under reflux for one hour,cooled to 10° C., and then stirred. The precipitated crystal wascentrifuged and washed with methanol (15 L). The separated crystal wasdried at 60° C. to obtain 7-(4-chlorobutoxy)-1H-quinolin-2-one (15.07kg).

Thereafter, water (20 L), potassium carbonate (1.84 kg),1-benzo[b]thiophen-4-yl-piperazine hydrochloride (3.12 kg), and ethanol(8 L) were mixed in a reaction vessel, and then stirred at 50° C.7-(4-Chlorobutoxy)-1H-quinolin-2-one (2.80 kg) was added to the mixture,and stirred under reflux for nine hours. After concentrating the solventto 8 L under ordinary pressure, the mixture was stirred at 90° C. forone hour, and then cooled to 9° C. The precipitated crystal wascentrifuged, and then sequentially washed with water (8 L) and ethanol(6 L). The separated crystal was dried at 60° C. to obtain a crudeproduct. The crude product (4.82 kg) and ethanol (96 L) were mixed in areaction vessel, and acetic acid (4.8 L) was introduced into thereaction vessel. The mixture was stirred under reflux for one hour todissolve the crude product. After introducing hydrochloric acid (1.29kg), the mixture was cooled to 10° C. The mixture was heated again,refluxed for one hour, and cooled to 7° C. The precipitated crystal wascentrifuged and washed with ethanol (4.8 L). The separated crystal wasdried at 60° C. to obtain7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onehydrochloride (5.09 kg). The resulting7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onehydrochloride (5.00 kg), ethanol (45 L), and water (30 L) were mixed ina reaction vessel. The mixture was stirred under reflux to dissolve the7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onehydrochloride. Activated carbon (500 g) and water (5 L) were addedthereto, and an activated carbon treatment was conducted under refluxfor 30 minutes. After performing hot filtration, a solution containingsodium hydrate (511 g) dissolved in water (1.5 L) was flowed into thereaction vessel while stirring the filtrate under reflux. After stirringunder reflux for 30 minutes, water (10 L) was introduced thereto, andthe mixture was cooled to approximately 40° C. The precipitated crystalwas centrifuged and washed with water (125 L). The separated crystal wasdried at 80° C. to obtain7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one(3.76 kg).

The7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one(3.2 kg) obtained above, ethanol (64 L), water (74 L), and acetic acid(1.77 kg) were mixed in a reaction vessel to prepare an acid liquidmixture. The liquid mixture was stirred under reflux to dissolve the7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one(reflux temperature: 84° C.). After cooling to −5° C., the solutionobtained above was introduced, over a period of 30 minutes, into asolution containing 25% sodium hydroxide (5.9 kg) and water (54 L) thatwas cooled to 0° C., to prepare a liquid mixture with pH10. Afterstirring at 5° C. or below for one hour, the mixture was heated to 20 to0.30° C. and further stirred for seven hours to conduct solid-liquidseparation. Washing with water (320 L) was performed until alkali in thesolid component disappeared (i.e., until the pH value of the filtratebecame 7). The solid component was then air-dried until its weightbecame constant (i.e., until there was no longer any change of weightobserved) to obtain a white solid7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onedihydrate (unground, 3.21 kg).

FIG. 1 shows the ¹H-NMR spectrum (DMSO-d₆, TMS) of the dihydratesynthesized by the aforesaid method. As shown in FIG. 1, in the ¹H-NMRspectrum (DMSO-d₆, TMS), peaks were observed at 1.64 ppm (tt, J=7.4 Hz,J=7.4 Hz, 2H), 1.80 ppm (tt, J=7.0 Hz, J=7.0 Hz, 2H), 2.44 ppm (t, J=7.5Hz, 2H), 2.62 ppm (br, 4H), 3.06 ppm (br, 4H), 3.32 ppm (s, 4H+H₂O),4.06 ppm (t, J=6.5 Hz, 2H), 6.29 ppm (d, J=9.5 Hz, 1H), 6.80 ppm (d,J=2.5 Hz, 1H), 6.80 ppm (dd, J=2.5 Hz, J=9.0 Hz, 1H), 6.88 ppm (d, J=7.5Hz, 1H), 7.27 ppm (dd, J=7.8 Hz, J=7.8 Hz, 1H), 7.40 ppm (dd, J=0.5 Hz,J=5.5 Hz, 1H), 7.55 ppm (d, J=9.0 Hz, 1H), 7.61 ppm (d, J=8.0 Hz, 1H),7.69 ppm (d, J=5.5 Hz, 1H), 7.80 ppm (d, J=9.5 Hz, 1H), and 11.57 ppm(s, 1H).

The X-ray powder diffraction spectrum of the dihydrate synthesized bythe aforesaid method was measured using an X-ray diffractometer (D8ADVANCE, produced by Bruker AXS). FIG. 2 shows the X-ray powderdiffraction spectrum. As shown in FIG. 2, in the X-ray powderdiffraction spectrum, diffraction peaks were observed at 2θ=8.1°, 8.9°,15.1°, 15.6°, and 24.4°. Other than those mentioned above, diffractionpeaks were also observed at 2θ=11.6°, 12.2°, 14.0°, 16.3°, 18.1°, 18.4°,18.9°, 19.5°, 20.5°, 21.5°, 22.6°, 23.3°, 25.0°, 26.1°, 26.4°, 27.1°,28.1°, 28.5°, 28.9°, 29.8°, 30.4°, 30.7°, 31.6°, 32.9°, 33.9°, 34.4°,35.2°, 36.0°, 36.7°, 37.4°, and 38.3°.

The IR (KBr) spectrum of the dihydrate synthesized by the aforesaidmethod was measured. FIG. 3 shows the IR (KBr) spectrum. As shown inFIG. 3, in the IR (KBr) spectrum, absorption bands were observed in thevicinity of wavenumbers 3509 cm⁻¹, 2934 cm⁻¹, 2812 cm⁻¹, 1651 cm⁻¹, 1626cm⁻¹, 1447 cm⁻¹, 1223 cm⁻¹ and 839 cm⁻¹.

The Raman spectrum of the dihydrate synthesized by the aforesaid methodwas measured. FIG. 4 shows the Raman spectrum. As shown in FIG. 4, inthe Raman spectrum, absorption bands were observed in the vicinity ofwavenumbers 1497 cm⁻¹, 1376 cm⁻¹, 1323 cm⁻¹, 131.1 cm⁻¹, 1287 cm⁻¹, 1223cm⁻¹, and 781 cm⁻¹.

Other than those mentioned above, absorption was also observed in thevicinity of wavenumbers 1656 cm⁻¹, 1613 cm⁻¹, 1563 cm⁻¹, 1512 cm⁻¹, 1468cm⁻¹, 1446 cm⁻¹, 1241 cm⁻¹, 1203 cm⁻¹, 1145 cm⁻¹, 1096 cm⁻¹, 1070 cm⁻¹,971 cm⁻¹, and 822 cm⁻¹.

Furthermore, the water content of the dihydrate synthesized by theaforesaid method was measured using a moisture meter (CA-100, producedby Mitsubishi Chemical Analytech Co., Ltd.) by the Karl Fischer method.The results showed that the dihydrate had a water content of 7.79% byweight.

Production Example 2 Synthesis of Finely Ground Dihydrate

Dihydrate crystal (2.73 kg) obtained in Production Example 1 was groundusing a jet mill. Here, the air pressure was set at 5 kgf/cm², and therotational speed of the feeder was set at 20 rpm. As a result, finelyground7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onedihydrate (2.61 kg, 95.6%) was obtained.

The dihydrate (finely ground product) thus obtained had a mean particlediameter of 5.5 μm. The mean particle diameter was measured using aMicrotrack HRA, produced by Nikkiso Co., Ltd.

FIG. 5 shows the ¹H-NMR spectrum (DMSO-d₆, TMS) of the dihydratesynthesized by the above method. As shown in FIG. 5, in the ¹H-NMRspectrum (DMSO-d₆, TMS), peaks were observed at 1.64 ppm (tt, J=7.3 Hz,J=7.3 Hz, 2H), 1.80 ppm (tt, J=6.9 Hz, J 6.9 Hz, 2H), 2.44 ppm (t, J=7.3Hz, 2H), 2.62 ppm (br, 4H), 3.06 ppm (br, 4H), 3.32 ppm (s, 4H+H₂O),4.06 ppm (t, J=6.5 Hz, 2H), 6.29 ppm (d, J=9.5 Hz, 1H), 6.80 ppm (d,J=2.5 Hz, 1H), 6.80 ppm (dd, J=2.3 Hz, J=9.3 Hz, 1H), 6.88 ppm (d, J=7.5Hz, 1H), 7.27 ppm (dd, J=8.0 Hz, J=8.0 Hz, 1H), 7.40 ppm (d, J=5.5 Hz,1H), 7.55 ppm (d, J=9.5 Hz, 1H), 7.62 ppm (d, J=8.0 Hz, 1H), 7.69 ppm(d, J=5.5 Hz, 1H), 7.80 ppm (d, J=9.5 Hz, 1H), and 11.57 ppm (s, 1H).

The X-ray powder diffraction spectrum of the dihydrate synthesized bythe aforesaid method was measured in the same manner as in ProductionExample 1. FIG. 6 shows the X-ray powder diffraction spectrum. As shownin FIG. 6, in the X-ray powder diffraction spectrum, diffraction peakswere observed at 2θ=8.2°, 8.9°, 15.2°, 15.7°, and 24.4°.

Other than those mentioned above, diffraction peaks were also observedat 28=6.8°, 12.2°, 14.0°, 14.5°, 17.4°, 1.8.1°, 18.5°, 19.0°, 19.2°,19.6°, 20.3°, 20.6°, 21.5°, 22.7°, 23.4°, 25.0°, 26.1°, 27.1°, 28.6°,29.0°, 30.4°, 34.0°, 34.5°, 35.3°, and 36.7°.

The IR (KBr) spectrum of the dihydrate synthesized by the aforesaidmethod was measured in the same manner as in Production Example 1. FIG.7 shows the IP (KBr) spectrum. As shown in FIG. 7, in the IP (KBr)spectrum, absorption bands were observed in the vicinity of wavenumbers3507 cm⁻¹, 2936 cm⁻¹, 2812 cm⁻¹, 1651 cm⁻¹, 1626 cm⁻¹, 1447 cm⁻¹, 1223cm⁻¹, and 839 cm⁻¹.

The Raman spectrum of the dihydrate synthesized by the aforesaid methodwas measured. FIG. 8 shows the Raman spectrum. As shown in FIG. 8, inthe Raman spectrum, absorption bands were observed in the vicinity ofwavenumbers 1496 cm⁻¹, 1376 cm⁻¹, 1323 cm⁻¹, 1311 cm⁻¹, 1286 cm⁻¹, 1223cm⁻¹, and 781 cm⁻¹.

Other than those mentioned above, absorption was also observed in thevicinity of wavenumbers 1656 cm⁻¹, 1614 cm⁻¹, 1563 cm⁻¹, 1512 cm⁻¹, 1467cm⁻¹, 1446 cm⁻¹, 1241 cm⁻¹, 1203 cm⁻¹, 1145 cm⁻¹, 1095 cm⁻¹, 1069 cm⁻¹,971 cm⁻¹, and 822 cm⁻¹.

Furthermore, the water content of the dihydrate synthesized by theaforesaid method was measured using a moisture meter (CA-100, producedby Mitsubishi Chemical Analytech Co., Ltd.) by the Karl Fischer method.The results showed that the dihydrate had a water content of 6.74% byweight.

Production Example 3 Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onehydrate

7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one(5.0 kg), ethanol (100 L), water (115 L), and DL-lactic acid (2.29 kg)were mixed to prepare an acid liquid mixture. The liquid mixture wasstirred under reflux to dissolve the7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one(reflux temperature: 82° C.). After cooling to −5° C., the solutionobtained above was introduced, over a period of about 15 minutes, into asolution containing sodium hydroxide (1.48 kg) and water (135 L) thatwas cooled to 1° C., to prepare a liquid mixture with pH11. After beingstirred at approximately 2 to 5° C. for three hours, the mixture washeated to 45° C. and further stirred at 45 to 50° C. for two hours toconduct solid-liquid separation. Washing with water (200 L) wasperformed until alkali in the solid component disappeared (i.e., untilthe pH value of the filtrate became 7). The solid component was furtherwashed with a liquid mixture of ethanol (15 L) and water (20 L). Thesolid component was then dried at room temperature until its weightbecame constant to obtain a white solid7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onedihydrate (unground, 5.11 kg).

The hydrate thus obtained was the same as that obtained in ProductionExample 1.

The Raman spectrum of the hydrate synthesized by the aforesaid methodwas measured. FIG. 9 shows the Raman spectrum. As shown in FIG. 9, inthe Raman spectrum, absorption bands were observed in the vicinity ofwavenumbers 1497 cm⁻¹, 1376 cm⁻¹, 1323 cm⁻¹, 1311 cm⁻¹, 1287 cm⁻¹, 1223cm⁻¹, and 782 cm⁻¹.

Other than those mentioned above, absorption was also observed in thevicinity of wavenumbers 1656 cm⁻¹, 1614 cm⁻¹, 1563 cm⁻¹, 1512 cm⁻¹, 1468cm⁻¹, 1446 cm⁻¹, 1241 cm⁻¹, 1203 cm⁻¹, 1145 cm⁻¹, 1126 cm⁻¹, 1096 cm⁻¹,1070 cm⁻¹, 972 cm⁻¹, and 822 cm⁻¹.

Production Example 4 Synthesis of Anhydride of Compound (I)

The7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one(700 g) synthesized in Production Example 1, ethanol (14 L), and aceticacid (1.4 L) were mixed in a reaction vessel. The mixture was heated tothe reflux temperature (76° C.) to dissolve the7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one.Concentrated hydrochloric acid (158 mL) was added thereto, and thencooled to 10° C. while being stirred. Thereafter, the mixture was heatedagain, stirred under reflux for one hour, and then cooled to 10° C. orless. The precipitated solid was filtered by suction and washed withethanol (0.7 L). The solid component was then air-dried at 60° C. untilits weight became constant to obtain a white solid7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onehydrochloride (814 g). 7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-ylbutoxy]-1H-quinolin-2-one hydrochloride (800 g), ethanol (7.2 L), andwater (4.8 L) were mixed in a reaction vessel, and the mixture washeated to the reflux temperature (8° C.) while being stirred. Afterperforming hot filtration, the7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onehydrochloride was dissolved. A solution containing sodium hydrate (81.6g) dissolved in water (240 mL) was flowed into the above-obtainedsolution, and the mixture was stirred under reflux for 30 minutes. Water(2.4 L) was fed to the mixture, followed by cooling to 40° C. whilestirring. The precipitated solid was filtered out and washed with water(16 L). The solid was dried at 80° C. to obtain a white solid7-[4-(4-benzo[b]thiophen-4-yl-piperazin-2-yl)butoxy]-1H-quinolin-2-oneanhydride (637 g).

The ¹H-NMR spectrum of the anhydride obtained above was measured in thesame manner as in Production Example 1. FIG. 10 shows the ¹H-NMRspectrum (DMSO-d₆, TMS). As shown in FIG. 10, in the ¹H-NMR spectrum(DMSO-d₆, TMS), peaks were observed at 1.63 ppm (tt, J=7.3 Hz, J=7.1 Hz,2H), 1.80 ppm (tt, J=7.3 Hz, J=6.3 Hz, 2H), 2.44 ppm (t, J=7.1 Hz, 2H),2.61 ppm (m, 4H), 3.05 ppm (m, 4H), 4.05 ppm (t, J=6.3 Hz, 2H), 6.29 ppm(d, J=9.5 Hz, 1H), 6.80 ppm (d, J=2.5 Hz, 1H), 6.80 (dd, J=9.4 Hz, J=2.5Hz, 1H), 6.88 ppm (dd, J=7.8 Hz, 0.8 Hz, 1H), 7.27 ppm (dd, J=7.8 Hz,J=7.8 Hz, 1H), 7.39 ppm (dd, J=5.6 Hz, 0.8 Hz, 1H), 7.55 ppm (d, J=9.4Hz, 1H), 7.61 ppm (d, J=7.8 Hz, H), 7.69 ppm (d, J=5.6 Hz, 1H), 7.80 ppm(d, J=9.5 Hz, 1H), and 11.60 (s, 1H).

The X-ray powder diffraction spectrum of the anhydride obtained abovewas measured in the same manner as in Production Example 1. FIG. 11shows the X-ray powder diffraction spectrum. As shown in FIG. 11, in theX-ray powder diffraction spectrum, diffraction peaks were observed at2θ=14.4°, 19.1°, 20.2°, 21.3°, and 23.2°.

The IR (KBr) spectrum of the anhydride obtained above was measured inthe same manner as in Production Example 2. FIG. 12 shows the IR (KBr)spectrum. As shown in FIG. 12, the7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onehad absorption bands in the IR (KBr) spectrum in the vicinity ofwavenumbers 2941 cm⁻¹, 2818 cm⁻¹, 3655 cm⁻¹, 1624 cm⁻¹, 1449 cm⁻¹, 1221cm⁻¹, and 833 cm⁻¹.

The water content of the anhydride synthesized by the aforesaid methodwas measured in the same manner as in Production Example 2. The resultsrevealed that the anhydride obtained above had a water content of 0.04%by weight.

Injectable Preparation

injectable preparations described below were produced using a dihydrateof Compound (I) (the dihydrate obtained in Production Example 1 wasground into a desirable particle size) or an anhydride of Compound (I),both produced by the method described above, and the followingcomponents. Unless otherwise defined, dihydrate of Compound (1), andanhydrate of Compound (I) were used after being ground into 2 to 6 μm.The particle size was measured using a laser diffraction particle sizeanalyzer (SALD-3000J or SALD-3100, produced by Shimadzu Corporation).When an injectable preparation contains 108 mg of dihydrate of Compound(I) per 1 mL of the preparation, 100 mg of Compound (I) is contained inthe injectable preparation.

Polyethylene glycol 400 (Macrogol 400, produced by Wako Pure ChemicalIndustries)

Sodium chloride (produced by Nacalai Tesque, Inc.)

Sodium dihydrogenphosphate dihydrate (produced by Nacalai Tesque, Inc.)

Disodium hydrogenphosphate dodecahydrate (produced by Wako Pure ChemicalIndustries)

Polyoxyethylene sorbitan mono-fatty acid ester (polysorbate 80, producedby NOF Corporation)

DL-methionine (produced by Wako Pure Chemical Industries)

Polyoxyethylene (160) polyoxypropylene (30) glycol (Pluronic F68,produced by BASF Japan Ltd.)

Sodium hydroxide (produced by Wako Pure Chemical Industries)

Sorbitol (D(−)-sorbitol, produced by Wako Pure Chemical Industries)

Sodium carboxymethylcellulose (Sodium carboxymethyl cellulose, producedby Hercules Chemical Co., Ltd.)

Benzyl benzoate (produced by Nacalai Tesque, Inc.)

Example 1 Synthesis of Injectable Preparation Comprising an AqueousParticle Binder-Containing Anhydride of Compound (I) as an ActiveIngredient

Polyethylene glycol 400 (8640 mg), polyoxyethylene (160)polyoxypropylene (30) glycol (300 mg), sodium chloride (12000 mg),DL-methionine (750 mg), sodium dihydrogenphosphate dihydrate (226 mg),disodium hydrogenphosphate dodecahydrate (176 mg), and polysorbate 80(90 mg) were, as a vehicle, weighed and mixed in a 500 mL beaker. Waterfor injection (240 mL) was added to dissolve the vehicle. Afterconfirming that the vehicle was completely dissolved in the water forinjection, the resulting solution was made to pass through apolyethersulfone (PES) filter (Millipore Express PLUS high flow rate, 73mm/0.22 μm, SCGP U11 RE, produced by Nihon Millipore K. K.) in a cleanbench (biological clean bench, MCV-B161F, produced by Biomedix). Ananhydride of Compound (I) (30000 mg) was added to the solution that hadbeen passed through the filter in the clean bench to make a suspension.The mixture was adjusted to have a pH value of about 7 using a IN or 5Nsodium hydroxide that had been passed through a PES filter. The volumeof the resulting solution was measured using a measuring cylinder, and aportion thereof (0.5 mL) was extracted. After measuring the content ofCompound (I) by the HPLC method, water for injection was added theretoto adjust the concentration of Compound (I) to 100 mg/mL.

Thereafter, each formulation was individually placed in a vial (φ23×35and an opening of 13 mm, produced by Iwata Glass Industrial Co., Ltd.),and then processed in an autoclave (121° C., 20 minutes) to obtain aninjectable preparation. The resulting injectable preparation had a pHvalue of 6.54.

The particle diameter of the anhydride of Compound (I) contained in theresulting injectable preparation was measured using a laser diffractionparticle size analyzer (SALD-3000J or SALD-3100, produced by ShimadzuCorporation). Specifically, the secondary mean particle diameter wasdefined as the particle diameter measured using a circulation cell andusing water as the measurement medium. The mean primary particlediameter was defined as the particle diameter measured under the sameconditions as described above except that the measurement was performedwhile the measurement medium was subjected to ultrasonic irradiation.(This is also true for the Examples described below.) The anhydride ofCompound (I) had a secondary mean particle diameter of 10.480 μm. It wasconfirmed that particles of the anhydride of Compound (I) aggregated toform secondary particles.

Example 2 Synthesis of Injectable Preparation Comprising an AqueousParticle Binder-Containing Dihydrate of Compound (I) as an ActiveIngredient

An injectable preparation was produced in the same manner as in Example1, except that dihydrate of Compound (I) was used instead of anhydrideof Compound (I) and the autoclave process was not performed. Theresulting injectable preparation had a pH value of 7.08.

The particle diameter of the dihydrate of Compound (I) contained in theresulting injectable preparation was measured in the same manner as inExample 1. The dihydrate of Compound (I) had a mean particle diameter of9.819 μm. It was confirmed that particles of the dihydrate of Compound(I) aggregated to form secondary particles.

Components of the injectable preparations obtained in Examples 1 and 2,and the amount of each component therein (i.e., the formulations ofinjectable preparations), are shown in Table 1 below.

TABLE 1 Amount (mg) Components Example 1 Example 2 Anhydride of Compound(I) 100 — Dihydrate of Compound (I) — 108 Polyethylene glycol 400 28.828.8 Sodium chloride 40 5 Sodium dihydrogenphosphate dihydrate 0.7560.756 Disodium hydrogenphosphate 0.588 0.588 dodecahydrate Polysorbate80 0.3 0.3 DL-methionine 2.5 2.5 Polyoxyethylene (160) 1 1polyoxypropylene (30) glycol Sodium hydroxide Q.S. Q.S. Water forinjection Q.S. Q.S. Total 1 mL 1 mL

The injectable preparation of Example 2 was re-produced in the samemanner (Example 2b). At the same time, an injectable preparation(Example 2c) using 10 mg/mL of sodium chloride instead of 5 mg/mL, andan injectable preparation (Example 2a) excluding polyethylene glycolfrom Example 2c were produced. Specifically, injectable preparations(Examples 2a, 2b, and 2c) as shown in Table 2 were produced.Furthermore, injectable preparations of Examples 2a, 2b, and 2c wereallowed to stand at 60° C. for one month and then their dispersibilityand redispersibility were analyzed. The mean primary particle diameterand mean secondary particle diameter were measured before and afterstanding. Table 2 also shows the results.

TABLE 2 Amount (mg) Components 2a 2b 2c Dihydrate of Compound (I) 108108 108 Polyethylene glycol 400 — 28.8 28.8 Sodium chloride 10 5 10Sodium dihydrogenphosphate 0.756 0.756 0.756 dihydrate Disodiumhydrogenphosphate 0.588 0.588 0.588 dodecahydrate Polysorbate 80 0.3 0.30.3 DL-methionine 2.5 2.5 2.5 Polyoxyethylene (160) 1 1 1polyoxypropylene (30) glycol Sodium hydroxide Q.S. Water for injectionQ.S. pH 7.0 Total 1 mL Dispersibility (60° C./1 M, Rf) 0.72 0.67 0.78Redispersibility (60° C./1 M) A A A Mean particle diameter (Initial, 4.45.0 4.9 μm) Upper column/Primary particle, 9.8 10.3 8.9 Lowercolumn/Secondary particle Mean particle diameter (60° C./1 M, 3.9 3.84.2 μm) Upper column/Primary particle, 10.3 10.4 10.8 Lowercolumn/Secondary particle

In the Table, the values shown in the column of “Dispersibility (60°C./1M, Rf)” indicate the multiple of the precipitation height formedupon allowing each injectable preparation to stand at 60° C. for onemonth after production relative to the liquid surface height.Specifically, the numbers indicate the ratio of the precipitation heightwhen the height of the liquid surface defined as 1. (60° C./1M meansthat the sample was allowed to stand at 60° C. for one month).

Furthermore, the “A” symbol in the column “Redispersibility (60° C./1M)”indicates that the injectable preparation easily returned to asuspension when gently shaken by hand after precipitation had occurreddue to standing at 60° C. for one month.

Example 3 Synthesis of Injectable Preparation Comprising an OilyParticle Binder-Containing Anhydride of Compound (I) as an ActiveIngredient

Carboxymethylcellulose was weighed (15000 mg) and placed in a 300 mLbeaker. Water for injection (120 mL) was added thereto, and thecarboxymethylcellulose was dissolved using a homogenizer (OMNI TH,produced by OMNI International Co., Ltd.) at 50° C. Subsequently,sorbitol (75000 mg), sodium dihydrogenphosphate dihydrate (117 mg), andpolysorbate 80 (150 mg) were weighed and added into the 300 mL beaker.The mixture was then fully stirred. After dissolving the resultingsolution was passed through a polyethersulfone (PES) filter (MilliporeExpress PLUS high flow rate, 73 mm/0.22 μm, SCGP U11 RE, produced byNihon Millipore K.K.) in a clean bench (biological clean bench,MCV-B161F, Biomedix, produced by Biomedix). In the clean bench, benzylbenzoate that had been passed through a polytetrafluoroethylene (PTFE)filter (Millex®-FG, 0.2 μm, 25 mm, produced by Nihon Millipore K.K.,sterilized by ethylene oxide) was added to the 10 mL-line of a measuringflask whose tare weight was weighed in advance. Then, the weight of themeasuring flask was measured. The amount of benzyl benzoate necessary toadd was estimated based on the density calculated from the weightmeasured. The necessary amount of benzyl benzoate was added to thesolution passed through a PES filter, and then fully mixed. An anhydrideof Compound (I) (16215 mg) weighed in the clean bench was added thereto.The mixture was adjusted to have a pH value of about 7 using a IN or 5Nsodium hydroxide that had been passed through a PES filter. The volumethereof was measured using a measuring cylinder, and a portion thereof(0.5 mL) was extracted. After measuring the content of Compound (I) bythe HPLC method, water for injection was added thereto to adjust theconcentration of Compound (I) to 100 mg/mL. The resulting injectablepreparation had a pH value of 6.95.

The particle diameter of the anhydride of Compound (I) contained in theresulting injectable preparation was measured in the same manner as inExample 1. The anhydride of Compound (I) had a mean particle diameter of13.237 μm. It was confirmed that particles of the anhydride of Compound(I) aggregated to form secondary particles.

Example 4 Synthesis of Injectable Preparation Comprising an OilyParticle Binder-Containing Dihydrate of Compound (I) as an ActiveIngredient

An injectable preparation was produced in the same manner as in Example3, except that a dihydrate of Compound (I) was used instead of ananhydride of Compound (I). The resulting injectable preparation had a pHvalue of 7.06.

The particle diameter of the dihydrate of Compound (I) contained in theresulting injectable preparation was measured in the same manner as inExample 1. The dihydrate of Compound (I) had a mean particle diameter of8.025 μm. It was confirmed that particles of the dihydrate of Compound(I) aggregated to form secondary particles.

Components of the injectable preparations obtained in Examples 3 and 4,and the amount of each component therein, are shown in Table 3 below.

TABLE 3 Amount (mg) Components Example 3 Example 4 Anhydride of Compound(I) 100 — Dihydrate of Compound (I) — 108 Sorbitol 50 45 Sodiumcarboxymethylcellulose 10 10 Sodium dihydrogenphosphate 0.78 0.624dihydrate Disodium hydrogenphosphate — 2.148 dodecahydrate Benzylbenzoate 0.3 0.8 Polysorbate 80 1 1 Sodium hydroxide Q.S. Q.S. Water forinjection Q.S. Q.S. Total 1 mL 1 mL

The injectable preparation of Example 4 was then re-produced in the samemanner (Example 4b). At the same time, injectable preparations wereproduced in the same manner except that benzyl benzoate was used in anamount of 0.6 mg/mL (Example 4a) or 1.0 mg/mL (Example 4c) instead of0.8 mg/mL. Specifically, the injectable preparations (Examples 4a, 4b,and 4c) shown in Table 4 were produced. Furthermore, injectablepreparations of Examples 4a, 4b, and 4c were allowed to stand at 60° C.for one month, and then their dispersibility and redispersibility wereanalyzed. The mean primary particle diameter and mean secondary particlediameter were measured before and after standing. Table 4 also shows theresults.

TABLE 4 Amount (mg) Components 4a 4b 4c Dihydrate of Compound (I) 108108 108 Sorbitol 45 45 45 Sodium carboxymethylcellulose 10 10 10 Sodiumdihydrogenphosphate dihydrate 0.624 0.624 0.624 Disodiumhydrogenphosphate 2.148 2.148 2.148 dodecahydrate Benzyl benzoate 0.60.8 1 Polysorbate 80 1 1 1 Sodium hydroxide Q.S. Water for injectionQ.S. pH 7.0 Total 1 mL Dispersibility (60° C./1 M, Rf value) 0.64 0.800.73 Redispersibility (60° C./1 M) A A A Mean particle diameter Primary3.9 3.8 3.7 (Initial, μm) Secondary 8.0 7.6 7.5 Mean particle diameterPrimary 4.3 4.4 4.4 (60° C./1 M, μm) Secondary 11.9 11.6 11.6

The recitations in the columns in the Table above are the same as thosein Table 2.

The injectable preparations of Examples 1 and 3 were re-produced(Examples 1a and 3a), and the mean particle diameters thereof weremeasured. The results revealed that the injectable preparation ofExample 1a had a mean primary particle diameter of 5.0 μm and a meansecondary particle diameter of 10.3 μm, and the injectable preparationof Example 3a had a mean primary particle diameter of 3.9 μm and a meansecondary particle diameter of 15.1 μm.

Example 5

An injectable preparation was produced in the same manner as in Example3 except that a dihydrate of Compound (I) was used instead of ananhydride of Compound (I), benzyl alcohol (10 mg/mL) was used instead ofbenzyl benzoate (0.3 ng/mL). The secondary mean particle diameter of thedihydrate of Compound (I) in the injectable preparation was 6.9 μm andthe mean primary particle diameter thereof was 2.3 μm. From this result,it was confirmed that particles of the dihydrate of Compound (I)aggregated to form secondary particles. When the injectable preparationwas allowed to stand for four days at room temperature, precipitationoccurred but easily returned to a suspension when gently shaken by hand.

Test Examples 1 and 2

The injectable preparations comprising an anhydride of Compound (I) or adihydrate of Compound (I) produced in Examples 1 to 4 as an activeingredient were each injected into the crural muscle of male rats at adose of 25 mg/kg. To evaluate the transfer of Compound (I) into theblood after administration, blood samples were collected 0.25, 1, 3, 6,9, 14, 21, and 28 days after administration, and the concentration ofCompound (I) in the blood of each sample was measured.

FIG. 13 shows the mean blood concentration-time profiles obtained byadministering the injectable preparations produced in Examples 1 and 2.FIG. 14 shows the mean blood concentration-time profiles obtained byadministering the injectable preparations produced in Examples 3 and 4.As is clear from FIGS. 13 and 14, in either case in which the injectablepreparation comprising an anhydride or dihydrate of Compound (I) wasadministered, an effective blood concentration of Compound (I) wassustained for at least 28 clays. In particular, the results of TestExample 2 (FIG. 14) revealed that when an injectable preparationcontaining a dihydrate of Compound (I) produced in Example 4 wasadministered, an excessive increase in blood concentration was notobserved, and a stable blood concentration was obtained.

Test Example 3

The injectable preparations (Example A and Example B) shown in Table 5were produced in the same manner as in Examples 3 and 4, respectively.

TABLE 5 Amount (mg) Components Example A Example B Anhydride of Compound(I) 100 — Dihydrate of Compound (I) — 108 Sorbitol 50 50 Sodiumcarboxymethylcellulose 10 10 Sodium dihydrogenphosphate 0.78 0.78dihydrate Benzyl benzoate 1 0.8 Polysorbate 80 1 1 Sodium hydroxide Q.S.Q.S. (adjusted to (adjusted to pH 7) pH 7) Water for injection Q.S. Q.S.Total 1 mL 1 mL

The freeze-dried injectable preparations (Comparative Example A andComparative Example B) shown in Table 6 below were produced using thesame method as disclosed in the Example of JP2012-232958A. (The contentof JP2012-232958A is incorporated in this specification by reference.)The injectable preparations were produced at a 100-mL scale.

TABLE 6 Amount (mg) Comparative Comparative Components Example A ExampleB Anhydride of Compound (I) 100 — Dihydrate of Compound (I) — 108Mannitol 41.6 41.6 Sodium carboxymethylcellulose 8.32 8.32 Sodiumdihydrogenphosphate 0.78 0.624 dihydrate Sodium hydroxide Q.S. Q.S.(adjusted to (adjusted to pH 7) pH 7) Water for injection Q.S. Q.S.Total 1 mL 1 mL

The injectable preparations of Example A, Example B, Comparative ExampleA, and Comparative Example B were each injected into the crural muscleof male rats at a Compound (I) dose of 25 mg/kg. To evaluate thetransfer of Compound (I) into the blood after administration, bloodsamples were collected 0.25, 1, 3, 6, 9, 14, 21, and 28 days afteradministration, and the concentration of Compound (I) in the blood ofeach sample was measured. The freeze-dried injectable preparations ofComparative Examples A and B are such that Compound (I) or a saltthereof does not form secondary particles.

FIG. 15 shows the obtained results in the form of a graph. From FIG. 15,it was confirmed that, compared to the case in which secondary particlesare not formed, the injectable preparation of the present inventionwherein Compound (I) or a salt thereof forms secondary particles with aspecific particle diameter leads to a suppression of the burstphenomenon after the start of administration and renders excellentsustainability of medicinal efficacy.

Test Example 4

The injectable preparations having the compositions shown in Table 7(Examples C to F) were produced in the same manner as in Example 2.

TABLE 7 Amount (mg) Example Example Example Example Components C D E FDihydrate of Compound 108 108 108 108 (I) Sodium 0.756 0.756 0.756 0.756dihydrogenphosphate dihydrate Disodium 0.588 0.588 0.588 0.588hydrogenphosphate dodecahydrate Polysorbate 80 0.3 0.3 0.3 0.3 Sodiumchloride 10 5 10 5 DL-methionine 2.5 2.5 — — Polyoxyethylene (160) 1 1 11 polyoxypropylene (30) glycol Polyethylene glycol 400 — 28.8 — 28.8Sodium hydroxide Q.S. Q.S. Q.S. Q.S. (pH 7.0) (pH 7.0) (pH 7.0) (pH 7.0)Water for injection Q.S. Q.S. Q.S. Q.S. Total 1 mL 1 mL 1 mL 1 mL

The injectable preparations of Examples C to F were each injected intothe crural muscle of male rats at a Compound (1) dose of 25 mg/kg. Toevaluate the transfer of Compound (I) into the blood afteradministration, blood samples were collected 0.25, 1, 0.3, 6, 9, 14, 21,and 28 days after administration, and the concentration of Compound (I)in the blood of each sample was measured.

FIG. 16 shows the obtained results in a form of a graph. Table 8 showsC_(max) and AUC_(28day) after administering an injectable preparation ofeach Example.

TABLE 8 C_(max) AUC_(28 day) Formulation (ng/mL) (ng · day/mL) Example C26.2 ± 4.9 290.9 ± 43.3 Example D 36.9 ± 4.6 377.0 ± 26.9 Example E 21.7± 8.7 259.1 ± 75.2 Example F 28.3 ± 3.4 299.5 ± 21.9

From the results shown above, it was confirmed that the bloodconcentration of Compound (I) was maintained for a month from the timeof administration for all of the injectable preparations of Examples Cto F.

Test Example 5

Each vehicle component was dissolved in water for injection in the samemanner as in Example 2. A dihydrate of Compound (I) was suspended in theresulting injectable solutions to obtain injectable preparations(Examples G-1 to G-6, Examples H-1 to H-6, Example I-1 to I-6, andExamples J-1 to J-6) having the formulations shown in Tables 9 to 12.

TABLE 9 Examples G series Amount (mg) G-1 G-2 G-3 G-4 G-5 G-6 Dihydrateof Compound (I) 108 108 108 108 108 108 Macrogol 400 28.8 28.8 28.8 28.828.8 28.8 Sodium hydroxide 5 5 5 5 5 5 Sodium dihydrogenohosphate 0.7560.756 0.756 0.756 0.756 0.756 dihydrate Disodium hydrogenphosphate 0.5880.588 0.588 0.588 0.588 0.588 dodecahydrate Polysorbate 80 0.3 0.3 0.30.3 0.3 0.3 Polyoxyethylene (160) 0 0.1 0.3 1 3 10 polyoxypropylene (30)glycol Sodium hydroxide Q.S. Q.S. Q.S. Q.S. Q.S. Q.S. (adjusted(adjusted (adjusted (adjusted (adjusted (adjusted to pH 7) to pH 7) topH 7) to pH 7) to pH 7) to pH 7) Water for injection Q.S. Q.S. Q.S. Q.S.Q.S. Q.S. Total 1 mL 1 mL 1 mL 1 mL 1 mL 1 mL

TABLE 10 Examples H series Amount (mg) H-1 H-2 H-3 H-4 H-5 H-6 Dihydrateof Compound (I) 108 108 108 108 108 108 Macrogol 400 28.8 28.8 28.8 28.828.8 28.8 Sodium chloride 5 5 5 5 5 5 Sodium dihydrogenphosphate 0.7560.756 0.756 0.756 0.756 0.756 dihydrate Disodium hydrogenphosphate 0.5880.588 0.588 0.588 0.588 0.588 dodecahydrate Polysorbate 80 0 0 0 0 0 0Polyoxyethlene (160) 0 0.1 0.3 1 3 10 polyoxypropylene (30) glycolSodium hydroxide Q.S. Q.S. Q.S. Q.S. Q.S. Q.S. (adjusted (adjusted(adjusted (adjusted (adjusted (adjusted to pH 7) to pH 7) to pH 7) to pH7) to pH 7) to pH 7) Water for injection Q.S. Q.S. Q.S. Q.S. Q.S. Q.S.Total 1 mL 1 mL 1 mL 1 mL 1 mL 1 mL

TABLE 11 Examples I series Amount (mg) I-1 I-2 I-3 I-4 I-5 I-6 Dihydrateof Compound (I) 108 108 108 108 108 108 Macrogol 400 0 0 0 0 0 0 Sodiumchloride 5 5 5 5 5 5 Sodium dihydrogenphosphate 0.756 0.756 0.756 0.7560.756 0.756 dihydrate Disodium hydrogenphosphate 0.588 0.588 0.588 0.5880.588 0.588 dodecahydrate Polysorbate 80 0.3 0.3 0.3 0.3 0.3 0.3Polyoxyethylene (160) 0 0.1 0.3 1 3 10 polyoxypropylene (30) glycolSodium hydroxide Q.S. Q.S. Q.S. Q.S. Q.S. Q.S. (adjusted (adjusted(adjusted (adjusted (adjusted (adjusted to pH 7) to pH 7) to pH 7) to pH7) to pH 7) to pH 7) Water for injection Q.S. Q.S. Q.S. Q.S. Q.S. Q.S.Total 1 mL 1 mL 1 mL 1 mL 1 mL 1 mL

TABLE 12 Examples J series Amount (mg) J-1 J-2 J-3 J-4 J-5 J-6 Dihydrateof Compound (I) 108 108 108 108 108 108 Macrogol 400 0 0 0 0 0 0 Sodiumchloride 5 5 5 5 5 5 Sodium dihydrogenphosphate 0.756 0.756 0.756 0.7560.756 0.756 dihydrate Disodium hydrogenphosphate 0.588 0.588 0.588 0.5880.588 0.588 dodecahydrate Polysorbate 80 0 0 0 0 0 0 Polyoxyethylene(160) 0 0.1 0.3 1 3 10 polyoxypropylene (30) glycol Sodium hydroxideQ.S. Q.S. Q.S. Q.S. Q.S. Q.S. (adjusted (adjusted (adjusted (adjusted(adjusted (adjusted to pH 7) to pH 7) to pH 7) to pH 7) to pH 7) to pH7) Water for injection Q.S. Q.S. Q.S. Q.S. Q.S. Q.S. Total 1 mL 1 mL 1mL 1 mL 1 mL 1 mL

Table 13 shows the Rf value (the precipitation height when the height ofthe liquid surface defined as 1) of each Example.

The Rf values were measured after allowing each Example to stand at roomtemperature for five days while applying vibration. The test tube andvibration tester used for the measurement are as follows.

Test Tube into which Each Example was Filled

A test tube equipped with a screw top (NR-10, manufactured by MaruemuCorporation),Material (Body): Borosilicate glass,

Length: 105 mm,

Shape: Round bottom,

Capacity: 12 mL,

External diameter (φ)×Total height: φ26.5 mm×105 mm

Vibration Tester on which Each Test Tube was Placed

Air handling unit DH-14, manufactured by Sinko Industries Ltd.

(The air handling unit was used as a vibration tester by placing thereoneach test tube containing an injectable preparation.)

The vibration levels of the air handling unit were measured using avibration level meter (VM-53A, manufactured by RION Co., Ltd.), and thefollowing vibration levels were observed:

X-axis direction: 68 dB, Y-axis direction: 76 dB, and Z-axis direction:90 dB.

Application of vibration is considered to make the precipitate denser,facilitating the formation of a hard cake. Therefore, the conditions forthe measurement of Rf value described above are more severe thanstanding still.

FIG. 17 is a graph showing the results of Table 13. In Table 13 and FIG.17, PS80 stands for Polysorbate 80, PEG stands for Macrogol 400, and F68stands for polyoxyethylene (160) polyoxypropylene (30) glycol (PluronicF68). The symbol (+) appearing after some components means that thecomponent was contained therein, and the (−) indicates that thecomponent was not contained therein. This is also applicable to Table 14shown below.

TABLE 13 F68, F68, F68, F68, F68, F68, 0 mg 0.1 mg 0.3 mg 1 mg 3 mg 10mg PS80(−), PEG(−) 0.86 0.83 0.80 0.78 0.73 0.73 [Example J Series]PS80(+), PEG(−) 0.88 0.84 0.86 0.86 0.81 0.78 [Example I Series]PS80(−), PEG(+) 0.91 0.86 0.84 0.80 0.78 0.75 [Example H Series]PS80(+), PEG(+) 0.88 0.88 0.88 0.86 0.84 0.81 [Example G Series]

Test Example 6

The syringability of the injectable preparations of Examples G-1 to G-6,Examples H-1 to H-6, Examples I-1 to I-6, and Examples J-1 to J-6 wasevaluated as described below.

After production, the injectable preparations of Examples G-1 to G-6,Examples H-1 to H-6, Examples I-1 to I-6, and Examples J-1 to J-6 wereallowed to stand for five days while vibration was applied. Thereafter,the injectable preparations of Examples G-1 to G-6, Examples H-1 to H-6,Examples I-1 to I-6, and Examples J-1 to J-6 were inverted to redispersethe precipitates therein. The precipitates in all of the injectablepreparations were preferably redispersed by being inverted only once.

Thereafter, 500 μL of each injectable preparation was filled in asyringe equipped with a needle (27 G×1.5 inch, manufactured by TerumoCorporation), and then the injectability of each injectable preparationinto extracted muscle (chicken thigh) was confirmed. Table 14 shows theresults. In Table 14, “a” indicates that the entire quantity of theinjectable preparation could be injected (i.e., the syringability wassatisfactory); and “b” indicates that clogging of the syringe needleoccurred, and that the quantity of the injectable preparation could notbe injected in its entirety.

TABLE 14 F68, F68, F68, F68, F68, F68, 0 mg 0.1 mg 0.3 mg 1 mg 3 mg 10mg PS80(−), PEG(−) b b a a a a [Example J Series] PS80(+), PEG(−) b a aa a a [Example I Series] PS80(−), PEG(+) a a a a a a [Example H Series]PS80(+), PEG(+) a a a a a a [Example G Series]

1. An aqueous suspension comprising secondary particles formed by theaggregation of particles of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-oneor a salt thereof, the secondary particles having a mean particlediameter (a mean secondary particle diameter) of 1 to 50 μm and beingcontained in a dispersed state.
 2. The aqueous suspension according toclaim 1, wherein the particles of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-oneor a salt thereof have a mean primary particle diameter of 0.1 to 20 μm.3. The aqueous suspension according to claim 1 or 2, comprising7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-onein an amount of 0.1 to 40 wt %.
 4. An injectable preparation comprisingthe aqueous suspension according to any one of claims 1 to
 3. 5. Aninjectable preparation comprising7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-oneor a salt thereof, a particle binder, and water for injection, theparticle binder being at least one member selected from the groupconsisting of sodium chloride, polyvinylpyrrolidones (PVP),polyoxyethylene (160) polyoxypropylene (30) glycol, tocopherol,tocotrienol and esters thereof, tocopherol acetate, tocopherolsuccinate, benzyl alcohol, poorly water-soluble polyoxyethylene dioldibenzoate, poorly water-soluble polyoxyethylene diol dimethylsulfonicacid and esters thereof, and benzyl benzoate.
 6. The injectablepreparation according to claim 5, wherein the7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-oneor a salt thereof forms secondary particles and the secondary particleshave a mean secondary particle diameter of 1 to 50 μm.
 7. The injectablepreparation according to claim 5 or 6, comprising a suspension of the7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-oneor a salt thereof in water for injection.
 8. The injectable preparationaccording to claim 5 or 6, comprising a precipitate of the7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-oneor a salt thereof.
 9. The injectable preparation according to any one ofclaims 5 to 8, wherein the particle binder is at least one memberselected from the group consisting of sodium chloride, polyoxyethylene(160) polyoxypropylene (30) glycol, benzyl alcohol, and benzyl benzoate.10. The injectable preparation according to any one of claims 4 to 9,having a pH of 5 to
 8. 11. The injectable preparation according to anyone of claims 4 to 10, which is for treating or preventing relapse ofschizophrenia, bipolar disorder, or depression.
 12. The injectablepreparation according to any one of claims 4 to 11, wherein the7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-oneor a salt thereof is a dihydrate of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one.13. A prefilled syringe that is prefilled with the injectablepreparation according to any one of claims 4 to 12.